Substituted triazole derivatives as oxytocin antagonists

ABSTRACT

The present invention relates to a class of substituted 1,2,4-triazoles of formula (I) with activity as oxytocin antagonists, uses thereof, processes for the preparation thereof and compositions containing said inhibitors. These inhibitors have utility in a variety of therapeutic areas including sexual dysfunction, particularly premature ejaculation (P.E.).

This application is a division of U.S. patent application Ser. No.11/928,513 filed Oct. 30, 2007 which claims the benefit of U.S. patentapplication Ser. No. 10/944,959, filed on Sep. 20, 2004, which claimsthe benefit of United Kingdom Application Nos. 0322159.5, 0403150.6 and0415110.6, filed on Sep. 22, 2003, Feb. 12, 2004 and Jul. 5, 2004,respectively, and the benefit of U.S. Provisional Application Nos.60/535,846, 60/556,555 and 60/588,852, filed on Jan. 12, 2004, Mar. 26,2004 and Jul. 16, 2004, respectively.

The present invention relates to a class of substituted 1,2,4-triazoleswith activity as oxytocin antagonists, uses thereof, processes for thepreparation thereof and compositions containing said inhibitors. Theseinhibitors have utility in a variety of therapeutic areas includingsexual dysfunction, particularly premature ejaculation (P.E.).

Eur. J. Med. Chem. 1985, 20(3), pp 257-266, refers to derivatives of1,2,4-triazoles having analgesic and antiinflammatory properties. WO03/053437 refers to 1,2,4-triazoles having activity as oxytocinantagonists. EP 1,293,503 refers to derivatives of 1,2,4-triazoleshaving glycine transporter inhibiting properties.

SUMMARY OF INVENTION

The first aspect of the present invention provides for compounds offormula (I)

whereinV, W, X and Y, which may be the same or different, represent C—R⁶ or N;Z is C—H or N;R¹ is selected from:

-   -   (i) a phenyl ring substituted with two or more substituents,        which may be the same or different, each independently selected        from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, C(O)NR⁷R⁸, NR⁷R⁸,        NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂; and    -   (ii) a five to seven membered aromatic heterocyclic ring        containing 1-3 hetero atoms selected from N, O and S and        N-oxides thereof; said ring being optionally substituted with        two or more substituents, which may be the same or different,        selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂;        R² is selected from:    -   (i) H, OH, OR⁹, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂;    -   (ii) a 5-7 membered N-linked heterocycle containing 1-3        heteroatoms selected from N, O and S; said ring being optionally        substituted with one or more groups selected from (C₁-C₆)alkyl,        (C₁-C₆)alkoxy and C(O)NR⁷R⁸; and    -   (iii) (C₁-C₆)alkyl optionally substituted with an N-linked 5-7        membered heterocycle containing 1-3 heteroatoms selected from N,        O and S;        R³ is selected from H and (C₁-C₆)alkyl;        R⁴ is selected from H, (C₁-C₆)alkyl and OR⁹;        R⁵ is selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, NR⁷R⁸,        NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂;        R⁶ is selected from H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        NR⁷R⁸, NR⁷C(O)R¹⁰, N[C(O)R¹⁰]₂ and C(O)NR⁷R⁸;        R⁷ and R⁸, which may be the same or different, are selected from        H and (C₁-C₆)alkyl;        R⁹ is (C₁-C₆)alkyl, which is optionally substituted with one or        more groups each independently selected from (C₁-C₆)alkoxy and        an N-linked 5-7 membered heterocycle containing 1-3 heteroatoms        selected from N, O and S; and        R¹⁰ is selected from (C₁-C₆)alkyl and (C₁-C₆)alkoxy;        a tautomer thereof or a pharmaceutically acceptable salt,        solvate or polymorph of said compound or tautomer;        with the proviso that the compound of formula (I) is not

-   3-ethyl-5-(4-imidazol-1-ylphenyl)-4-(4-methoxyphenyl)-4H-[1,2,4]triazole,

-   3-(3′,5′-dichlorobiphenyl-4-yl)-4-(2-methoxyphenyl)-5-methyl-4H-[1,2,4]triazole,

-   3-(3′,5′-bis-trifluoromethylbiphenyl-4-yl)-4-(2-fluorophenyl)-5-methyl-4H-[1,2,4]triazole,    or

-   3-(3′,5′-bis-trifluoromethylbiphenyl-4-yl)-5-methyl-4-(3-trifluoromethylphenyl)-4H-[1,2,4]triazole.

Unless otherwise indicated, alkyl and alkoxy groups may be straight orbranched and contain 1 to 6 carbon atoms and preferably 1 to 4 carbonatoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, pentyl and hexyl. Examples of alkoxyinclude methoxy, ethoxy, isopropoxy and n-butoxy.

Halo means fluoro, chloro, bromo or iodo and is preferably fluoro.

A heterocycle may be saturated, partially saturated or aromatic.Examples of heterocyclic groups are thiolanyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, sulfolanyl, dioxolanyl, dihydropyranyl,tetrahydropyranyl, piperidinyl, pyrazolinyl, pyrazolidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, azepinyl,oxazepinyl, thiazepinyl, thiazolinyl and diazapanyl. Examples ofaromatic heterocyclic groups are furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl.

Unless otherwise indicated, the term substituted means substituted byone or more defined groups. In the case where groups may be selectedfrom a number of alternative groups, the selected groups may be the sameor different.

Preferred aspects of the invention are defined below.

In a preferred aspect, the present invention comprises compounds offormula (I) wherein

1 or 2 of the groups V, W, X and Y represent N when the remainderrepresent C—R⁶;

Z is C—H or N;

R¹ is selected from:

-   -   (i) a phenyl ring substituted with two or more substituents,        which may be the same or different, each independently selected        from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, C(O)NR⁷R⁸, NR⁷R⁸,        NR C(O)R¹⁰ and N[C(O)R¹⁰]₂; and    -   (ii) a five to seven membered aromatic heterocyclic ring        containing 1-3 hetero atoms selected from N, O and S and        N-oxides thereof; said ring being optionally substituted with        two or more substituents, which may be the same or different,        selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂;        Preferably, R² is selected from:    -   (i) H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy, NR⁷R⁸, NR        C(O)R¹⁰ and N[C(O)R¹⁰]₂; and    -   (ii) a 5-7 membered N-linked heterocycle containing 1-3        heteroatoms selected from N, O and S; said ring optionally        substituted with one or more groups selected from (C₁-C₆)alkyl,        (C₁-C₆)alkoxy and C(O)NR⁷R⁸;        R³ is selected from H and (C₁-C₆)alkyl;        R⁴ is selected from H, (C₁-C₆)alkyl and OR⁹;        R⁵ is (C₁-C₃)alkyl, (C₁-C₃)alkoxy or NR⁷R⁸;        R⁶ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano or NR⁷R⁸;        R⁷ and R⁸, which may be the same or different, are selected from        H and (C₁-C₆)alkyl;        R⁹ is (C₁-C₆)alkyl optionally substituted with (C₁-C₆)alkoxy;        and        R¹⁰ is selected from (C₁-C₆)alkyl and (C₁-C₆)alkoxy;        a tautomer thereof or a pharmaceutically acceptable salt,        solvate or polymorph of said compound or tautomer.

In another preferred aspect, the present invention comprises compoundsof formula (I) wherein

1 or 2 of the groups V, W and Y represent N when the remainder representC—R⁶ and X is CH;

Z is C—H or N;

R¹ is selected from:

-   -   (i) a phenyl ring substituted with two substituents, which may        be the same or different, each independently selected from halo,        (C₁-C₃)alkyl, (C₁-C₃)alkoxy, and cyano; and    -   (ii) a pyridyl ring or N-oxide thereof each substituted with two        substituents, which may be the same or different, each        independently selected from halo, (C₁-C₃)alkyl, (C₁-C₃)alkoxy,        and cyano;        R² is selected from:    -   (i) H, (C₁-C₃)alkoxy, (C₁-C₃)alkoxy-(C₁-C₃)alkoxy and        N((C₁-C₃)alkyl)₂; and    -   (ii) a 5 membered N-linked heterocycle containing 1-3 nitrogen        atoms, said ring optionally substituted with C(O)NR⁷R⁸;        R³ is selected from H and (C₁-C₆)alkyl;        R⁴ is selected from H, (C₁-C₆)alkyl and OR⁹;        R⁵ is (C₁-C₃)alkyl, (C₁-C₃)alkoxy or NR⁷R⁸;        R⁶ is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy or NR⁷R⁸;        R⁷ and R⁸, which may be the same or different, are selected from        H and (C₁-C₆)alkyl; and        R⁹ is (C₁-C₆)alkyl optionally substituted with methoxy;        a tautomer thereof or a pharmaceutically acceptable salt,        solvate or polymorph of said compound or tautomer.

In another preferred aspect, the present invention comprises compoundsof formula (I) wherein

W and Y are each independently CH or N and X and V are each CH;

Z is N;

R¹ is a phenyl ring substituted with two substituents, which may be thesame or different, each independently selected from fluoro, chloro,methyl, methoxy, and cyano;

R² is selected from H, methoxy, ethoxy, 2-methoxyethoxy, dimethylamino,1,2,3-triazol-2-yl and pyrolidinyl, the latter being optionallysubstituted by CONH₂;

R³ is selected from H and (C₁-C₆)alkyl;

R⁴ is H; and

R⁵ is methoxy;

a tautomer thereof or a pharmaceutically acceptable salt, solvate orpolymorph of said compound or tautomer.

Preferred embodiments of the compounds of formula (I) according to theabove aspects are those that incorporate two or more of the followingpreferences.

Preferably, 1 or 2 of the groups V, W, X and Y represent N when theremainder represent C—R⁶.

In a preferred embodiment, X is CH.

In a preferred embodiment, 1 or 2 of the groups V, W and Y represent Nwhen the remainder represent C—R⁶ and X is CH;

Preferably, Y is N or CR⁶.

More preferably, V, W and Y are each independently CH, C—OCH₃ or N.

Most preferably, W and Y are each independently CH or N.

In the most preferred embodiment, W and Y are each independently CH or Nand X and V are each CH.

In a preferred embodiment, Z is N.

In another preferred embodiment, Z is CH.

Preferably, R¹ is selected from:

-   -   (i) a phenyl ring substituted with two or more substituents,        which may be the same or different, each independently selected        from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, C(O)NR⁷R⁸, NR⁷R⁸,        NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂; and    -   (ii) a five to seven membered aromatic heterocyclic ring        containing 1-3 hetero atoms selected from N, O and S and        N-oxides thereof; said ring being optionally substituted with        two or more substituents, which may be the same or different,        selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,        C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂;

More preferably, R¹ is selected from:

-   -   (i) a phenyl ring substituted with two substituents, which may        be the same or different, each independently selected from halo,        (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰        and N[C(O)R¹⁰]₂; and    -   (ii) a pyridyl ring or N-oxide thereof each substituted with two        substituents, which may be the same or different, each        independently selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        cyano, C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂.

Yet more preferably, R¹ is selected from:

-   -   (i) a phenyl ring substituted with two substituents, which may        be the same or different, each independently selected from halo,        (C₁-C₃)alkyl, (C₁-C₃)alkoxy and cyano; and    -   (ii) a pyridyl ring or N-oxide thereof each substituted with two        substituents, which may be the same or different, each        independently selected from halo, (C₁-C₃)alkyl, (C₁-C₃)alkoxy        and cyano.

In a preferred embodiment, R¹ is a phenyl ring substituted with twosubstituents, which may be the same or different, each independentlyselected from fluoro, chloro, methyl, methoxy and cyano.

In another preferred embodiment, R¹ is pyridine-N-oxide substituted withtwo methyl groups.

Preferably, R² is selected from:

-   -   (i) H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy, NR⁷R⁸,        NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂; and    -   (ii) a 5-7 membered N-linked heterocycle containing 1-3        heteroatoms selected from N, O and S; said ring optionally        substituted with one or more groups selected from (C₁-C₆)alkyl,        (C₁-C₆)alkoxy and C(O)NR⁷R⁸.

More preferably, R² is selected from:

-   -   (i) H, (C₁-C₃)alkoxy, (C₁-C₃)alkoxy-(C₁-C₃)alkoxy and        N((C₁-C₃)alkyl)₂; and    -   (ii) a 5 membered N-linked heterocycle containing 1-3 nitrogen        atoms, said ring optionally substituted with C(O)NR⁷R⁸.

Yet more preferably, R² is selected from H, methoxy, ethoxy,2-methoxyethoxy, dimethylamino, 1,2,3-triazol-2-yl and pyrolidinyl, thelatter being optionally substituted by CONH₂.

Most preferably, R² is selected from H and methoxy.

Preferably, R³ is H or (C₁-C₃)alkyl.

Most preferably, R³ is H.

Preferably, R⁴ is H, (C₁-C₃)alkyl or OR⁹.

More preferably, R⁴ is H, (C₁-C₃)alkyl or (C₁-C₃)alkoxy.

Most preferably, R⁴ is H, methyl or methoxy.

In a preferred embodiment, R⁴ is H.

Preferably, R⁵ is (C₁-C₃)alkyl, (C₁-C₃)alkoxy or NR⁷R⁸.

More preferably, R⁵ is (C₁-C₃)alkoxy or NR⁷R⁸.

Most preferably, R⁵ is methoxy or NHCH₃.

In a preferred embodiment, R⁵ is methoxy.

Preferably, R⁶ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano or NR⁷R⁸.

More preferably, R⁶ is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy or NR⁷R⁸.

Yet more preferably, R⁶ is H, (C₁-C₃)alkyl or (C₁-C₃)alkoxy.

Most preferably, R⁶ is H, methyl or methoxy.

In a preferred embodiment, R⁶ is H or methyl.

In a most preferred embodiment, R⁶ is H.

Preferably, R⁷ is H or (C₁-C₃)alkyl.

Most preferably, R⁷ is H or methyl.

Preferably, R⁸ is H or (C₁-C₃)alkyl.

Most preferably, R⁸ is H or methyl.

Preferably, R⁹ is (C₁-C₆)alkyl optionally substituted with(C₁-C₆)alkoxy.

More preferably, R⁹ is (C₁-C₆)alkyl optionally substituted with methoxy.

Most preferably, R⁹ is methyl.

Preferred compounds of formula (I) are:

-   2-(4-fluoro-2-methylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   2-(2,3-dimethylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   5-(4-fluoro-2-methylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   5-(2,3-dimethylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   1-[5-[5-(2,3-dimethylphenyl)-pyridin-2-yl]-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-ylmethyl]-pyrrolidine-(2S)-2-carboxylic    acid amide;-   5-(2,3-dimethylphenyl)-2-(5-pyrrolidin-1-ylmethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   2-(4-fluoro-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2,3-dimethylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(4-fluoro-2-methylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2,3-dimethylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(4-cyano-2-methylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(5-fluoro-2-methoxyphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(4-cyano-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine;-   5-(4-cyano-2-methylphenyl)-2-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridine;-   2-(5-fluoro-2-methoxyphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridine;-   2-(2-fluoro-5-methoxyphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2-fluoro-5-methyl    phenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2,5-difluorophenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(3,5-dimethylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2,5-dimethylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2,5-dichlorophenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2-fluoro-5-methoxyphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(3,5-difluoro-phenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2,3-dimethylphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine;-   2-(5-chloro-2-methoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine;-   2-(4-fluoro-2-methoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine;-   2-(5-fluoro-2-methoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine;-   2-(5-fluoro-2-methylphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine;-   2-methoxy-5-{3-[(2-methoxyethoxy)methyl]-5-[6-(2-methoxy-5-methylphenyl)pyridin-3-yl]-4H-1,2,4-triazol-4-yl}pyridine;-   2-(2-fluoro-3-methoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine;-   2-(3,5-difluorophenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine;-   2-(2,5-dimethoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine;-   2-(3-chloro-4-fluorophenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine;-   2-(3-fluoro-2-methoxyphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine;    and-   2-(3-fluoro-2-methoxy-phenyl)-5-[4-(6-methoxy-pyridin-3-yl)-5-methyl-4-H-[1,2,4]triazol-3-yl]-pyrazine;    -   and tautomers thereof and pharmaceutically acceptable salts,        solvates and polymorphs of said compound or tautomer.

Most preferred compounds of formula (I) are:

-   2-(4-fluoro-2-methylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   2-(2,3-dimethylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   5-(4-fluoro-2-methylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   5-(2,3-dimethylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   1-[5-[5-(2,3-dimethylphenyl)-pyridin-2-yl]-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-ylmethyl]-pyrrolidine-(2S)-2-carboxylic    acid amide;-   5-(2,3-dimethylphenyl)-2-(5-pyrrolidin-1-ylmethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine;-   2-(4-fluoro-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2,3-dimethylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(4-fluoro-2-methylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(2,3-dimethylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(4-cyano-2-methylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(5-fluoro-2-methoxyphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine;-   2-(4-cyano-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine;-   5-(4-cyano-2-methylphenyl)-2-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridine;-   2-(5-fluoro-2-methoxyphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridine;-   2-(3-fluoro-2-methoxyphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine;    and-   2-(3-fluoro-2-methoxy-phenyl)-5-[4-(6-methoxy-pyridin-3-yl)-5-methyl-4-H-[1,2,4]triazol-3-yl]-pyrazine;    -   and tautomers thereof and pharmaceutically acceptable salts,        solvates and polymorphs of said compound or tautomer.

Pharmaceutically acceptable salts of the compounds of formula (I)comprise the acid addition salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts.

Hemisalts of acids may also be formed, for example, hemisulphate salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of three methods:

-   (i) by reacting the compound of formula (I) with the desired acid;-   (ii) by removing an acid-labile protecting group from a suitable    precursor of the compound of formula (I) using the desired acid; or-   (iii) by converting one salt of the compound of formula (I) to    another by reaction with an appropriate acid or by means of a    suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric ornon-stoichiometric amount of one or more pharmaceutically acceptablesolvent molecules, for example, ethanol. The term ‘hydrate’ is employedwhen said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein the drug and host arepresent in stoichiometric or non-stoichiometric amounts. Also includedare complexes of the drug containing two or more organic and/orinorganic components which may be in stoichiometric ornon-stoichiometric amounts. The resulting complexes may be ionised,partially ionised, or non-ionised. For a review of such complexes, see JPharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

Hereinafter all references to compounds of formula (I) includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of formula (I) ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of formula (I).

As indicated, so-called ‘pro-drugs’ of the compounds of formula (I) arealso within the scope of the invention. Thus certain derivatives ofcompounds of formula (I) which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into compounds of formula (I) having the desired activity, forexample, by hydrolytic cleavage. Such derivatives are referred to as‘prodrugs’. Further information on the use of prodrugs may be found inPro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T.Higuchi and W. Stella) and Bioreversible Carriers in Drug Design,Pergamon Press, 1987 (ed. E. B. Roche, American PharmaceuticalAssociation).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include

-   (i) where the compound of formula (I) contains an alcohol    functionality (—OH), an ether thereof, for example, a compound    wherein the hydrogen of the alcohol functionality of the compound of    formula (I) is replaced by (C₁-C₆)alkanoyloxymethyl; and-   (ii) where the compound of formula (I) contains a primary or    secondary amino functionality (—NH₂ or —NHR where R≠H), an amide    thereof, for example, a compound wherein, as the case may be, one or    both hydrogens of the amino functionality of the compound of    formula (I) is/are replaced by (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Moreover, certain compounds of formula (I) may themselves act asprodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites ofcompounds of formula (I), that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include

-   (i) where the compound of formula (I) contains a methyl group, an    hydroxymethyl derivative thereof (—CH₃→—CH₂OH):-   (ii) where the compound of formula (I) contains an alkoxy group, an    hydroxy derivative thereof (—OR→—OH);-   (iii) where the compound of formula (I) contains a tertiary amino    group, a secondary amino derivative thereof (—NR¹R²→—NHR¹ or —NHR²);-   (iv) where the compound of formula (I) contains a secondary amino    group, a primary derivative thereof (—NHR¹→—NH₂);-   (v) where the compound of formula (I) contains a phenyl moiety, a    phenol derivative thereof (-Ph→-PhOH); and-   (vi) where the compound of formula (I) contains an amide group, a    carboxylic acid derivative thereof (—CONH₂→COOH).

Compounds of formula (I) containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of formula (I)contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where structural isomers are interconvertible viaa low energy barrier, tautomeric isomerism (‘tautomerism’) can occur.This can take the form of proton tautomerism in compounds of formula (I)containing, for example, an imino, keto, or oxime group, or so-calledvalence tautomerism in compounds which contain an aromatic moiety. Itfollows that a single compound may exhibit more than one type ofisomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula (I), including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition salts wherein the counterion is optically active, for example,d-lactate, or racemic, for example, dl-tartrate.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (I) contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of isopropanol, typically from 2% to 20%, and from 0 to 5% byvolume of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art—see, for example, Stereochemistry ofOrganic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York,1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagent in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Also within the scope of the invention are intermediate compounds ashereinafter defined, all salts, solvates and complexes thereof and allsolvates and complexes of salts thereof as defined hereinbefore forcompounds of formula (I). The invention includes all polymorphs of theaforementioned species and crystal habits thereof.

When preparing compounds of formula (I) in accordance with theinvention, it is open to a person skilled in the art to routinely selectthe form of intermediate which provides the best combination of featuresfor this purpose. Such features include the melting point, solubility,processability and yield of the intermediate form and the resulting easewith which the product may be purified on isolation.

Drug Product

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. They may be obtained,for example, as solid plugs, powders, or films by methods such asprecipitation, crystallization, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof). Generally, they will beadministered as a formulation in association with one or morepharmaceutically acceptable excipients. The term ‘excipient’ is usedherein to describe any ingredient other than the compound(s) of theinvention. The choice of excipient will to a large extent depend onfactors such as the particular mode of administration, the effect of theexcipient on solubility and stability, and the nature of the dosageform.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in Remington'sPharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Oral Administration

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules containing particulates, liquids, or powders,lozenges (including liquid-filled), chews, multi- and nano-particulates,gels, solid solution, liposome, films, ovules, sprays and liquidformulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsulesand typically comprise a carrier, for example, water, ethanol,polyethylene glycol, propylene glycol, methylcellulose, or a suitableoil, and one or more emulsifying agents and/or suspending agents. Liquidformulations may also be prepared by the reconstitution of a solid, forexample, from a sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up from 1weight % to 80 weight % of the dosage form, more typically from 5 weight% to 60 weight % of the dosage form. In addition to the drug, tabletsgenerally contain a disintegrant. Examples of disintegrants includesodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, croscarmellose sodium, crospovidone,polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose,lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinisedstarch and sodium alginate. Generally, the disintegrant will comprisefrom 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight% of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 weight % to 5 weight % of the tablet, and glidants may comprise from0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight %to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight %to about 90 weight % binder, from about 0 weight % to about 85 weight %diluent, from about 2 weight % to about 10 weight % disintegrant, andfrom about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms:Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, NewYork, 1980).

Consumable oral films for human or veterinary use are typically pliablewater-soluble or water-swellable thin film dosage forms which may berapidly dissolving or mucoadhesive and typically comprise a compound offormula (I), a film-forming polymer, a binder, a solvent, a humectant, aplasticiser, a stabiliser or emulsifier, a viscosity-modifying agent anda solvent. Some components of the formulation may perform more than onefunction.

The compound of formula (I) may be water-soluble or insoluble. Awater-soluble compound typically comprises from 1 weight % to 80 weight%, more typically from 20 weight % to 50 weight %, of the solutes. Lesssoluble compounds may comprise a greater proportion of the composition,typically up to 88 weight % of the solutes. Alternatively, the compoundof formula (I) may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides,proteins, or synthetic hydrocolloids and is typically present in therange 0.01 to 99 weight %, more typically in the range 30 to 80 weight%.

Other possible ingredients include anti-oxidants, colorants, flavouringsand flavour enhancers, preservatives, salivary stimulating agents,cooling agents, co-solvents (including oils), emollients, bulkingagents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared byevaporative drying of thin aqueous films coated onto a peelable backingsupport or paper. This may be done in a drying oven or tunnel, typicallya combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Pharmaceutical Technology On-line,25(2), 1-14, by Verma et al (2001). The use of chewing gum to achievecontrolled release is described in WO 00/35298.

Parenteral Administration

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents.

Formulations for parenteral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease. Thus compounds of the invention may be formulated as a solid,semi-solid, or thixotropic liquid for administration as an implanteddepot providing modified release of the active compound. Examples ofsuch formulations include drug-coated stents andpoly(dl-lactic-coglycolic)acid (PGLA) microspheres.

Topical Administration

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibres, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may beincorporated—see, for example, J Pharm Sci, 88 (10), 955-958, by Finninand Morgan (October 1999).

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Inhaled/Intranasal Administration

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the invention, a suitable powder base such as lactose orstarch and a performance modifier such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate, preferably the latter. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose andtrehalose.

A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μl to 100 μl. A typical formulation may comprisea compound of formula (I), propylene glycol, sterile water, ethanol andsodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example, PGLA. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from 2 to 30 mg of the compound offormula (I). The overall daily dose will typically be in the range 50 to100 mg which may be administered in a single dose or, more usually, asdivided doses throughout the day.

Rectal/Intravaginal Administration

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Ocular/Aural Administration

The compounds of the invention may also be administered directly to theeye or ear, typically in the form of drops of a micronised suspension orsolution in isotonic, pH-adjusted, sterile saline. Other formulationssuitable for ocular and aural administration include ointments,biodegradable (e.g. absorbable gel sponges, collagen) andnon-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

Other Technologies

The compounds of the invention may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubiliser. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in International Patent Applications Nos. WO91/11172, WO 94/02518 and WO 98/55148.

Kit-of-Parts

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

Dosage

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range 50 mg to 100 mgdepending, of course, on the mode of administration and efficacy. Forexample, oral administration may require a total daily dose of from 50mg to 100 mg. The total daily dose may be administered in single ordivided doses and may, at the physician's discretion, fall outside ofthe typical range given herein.

These dosages are based on an average human subject having a weight ofabout 60 kg to 70 kg. The physician will readily be able to determinedoses for subjects whose weight falls outside this range, such asinfants and the elderly.

For the avoidance of doubt, references herein to “treatment” includereferences to curative, palliative and prophylactic treatment.

DESCRIPTION OF INVENTION Processes

Compounds of general formula (I) where R² is H, R³ is H and where R¹,R⁴, R⁵, R⁶, X, V, W, Y and Z are as described herein may be preparedaccording to reaction scheme 1.

Compounds of formula (II) are either commercially available or can beprepared by analogy with the methods described in J. Org. Chem., 66(2),605-608; 2001 and UK Pat. Appl., 2219793, 20 Dec. 1989.

Alternatively, when V, W, X or Y=CR⁶, compounds of formula (II) can beprepared from commercial compounds using standard chemical reactions andtransformations of R⁶.

When R⁶ is alkoxy and preferably methoxy, R⁶ is incorporated bysubstitution of a functional group, preferably chloro, as exemplified inpreparations 84-86.

Compounds of formula (III) may be prepared from compounds of formula(II) by process step (i), which comprises reaction with hydrazinemonohydrate in a suitable solvent such as methanol or ethanol between−10° C. and reflux. Typical conditions comprise heating 1 equivalent ofaryl ester (II) and 1.2-3 equivalents of hydrazine monohydrate inmethanol at reflux for 18-48 hours.

Compounds of formula (IV) may be prepared from compounds of formula(III) by process step (ii), which comprises reaction withN,N-dimethylacetamide dimethyl acetal (available from Aldrich) in asuitable solvent such as N,N-dimethylformamide, N-methylpyrrolidine ortoluene followed by the addition of a suitable acid catalyst such astrifluoroacetic acid, para-toluenesulfonic acid, camphor sulfonic acid,or hydrochloric acid. Typical conditions comprise heating 1 equivalentof aryl hydrazide (III) and 1.3 equivalents of N,N-dimethylacetamidedimethyl acetal in N,N-dimethylformamide to 60° C. for 2 hours, followedby concentration in vacuo, addition of toluene and 0.025 equivalents ofpara-toluenesulfonic acid, which is then heated to reflux for 2 hours.

Compounds of formula (V) may be prepared from compounds of formula (IV)by process step (iii), which comprises reaction with a suitable anilineor 3-aminopyridine in the presence of a suitable acid, such astrifluoroacetic acid, para-toluenesulfonic acid, camphor sulfonic acid,or hydrochloric acid in a suitable solvent, such as xylene, heated at150° C. Typical conditions comprise heating 1 equivalent of1,2,4-oxadiazole (IV), 2-3 equivalents of aniline or aminopyridine and0.04-0.1 equivalents of para-toluenesulfonic acid in xylene at 150° C.for 18-23 hours.

Compounds of formula (I) may be prepared from compounds of formula (V)by process step (iv), which comprises a Suzuki coupling reaction with asuitable boronic acid such as 2,3-dimethylphenyl boronic acid(commercially available), in a suitable solvent, in the presence of abase and a palladium catalyst such as[2-[(Dimethylamino-κN)methyl]phenyl-κC](tricyclohexylphosphine)(trifluoroacetato-κO-(SP-4-3)-palladium, prepared as described inOrganometallics, 2003, 22 (5), 987-999.

The Suzuki coupling reaction can be carried out as described in theliterature: Suzuki, A. Pure & Appl. Chem. 1985, 57, 1749 and referencecontained within; Angew. Chem. Int. Ed. 2002, 41, 4176-4211 andreferences contained within. Typical conditions comprise heating 1equivalent of aryl bromide (V), 2.5 equivalents of boronic acid, 3equivalents cesium carbonate. 0.06 equivalents of palladium catalystfrom preparation 3 in 1,4-dioxane at 120° C. for 4 hours.

Compounds of general formula (I) where R³ is H and where R¹, R², R⁴, R⁵,R⁶, X, V, W, Y and Z are as described herein, except R² #H, may beprepared according to reaction scheme 2.

Compounds of formula (VI) can be prepared from aryl hydrazides offormula (III) by process step (v), which comprises reaction with an acidchloride, such as methoxyacetyl chloride (for R²═OCH₃), in the presenceof base such as triethylamine, N-methyl morpholine, sodium carbonate orpotassium hydroxide. Typical conditions comprise heating 1.0 equivalentsof aryl hydrazide (III), 1.0-1.3 equivalents of acid chloride, 1.2-2.0equivalents of N-methyl morpholine in dichloromethane at 0-25° C. for3-18 hours.

Compounds of formula (VII) can be prepared from compound (VI) by processstep (vi), which comprises reaction with a suitable dehydrating agentsuch as phosphorous oxychloride, trifluoromethanesulfonic anhydride, orphosphorous pentachloride between a temperature of 25° C. and 110° C.Typical conditions comprise heating 1.0 equivalents of (VI) inphosphorous oxychloride at 110° C. for 4 hours.

Compounds of formula (VIII) may be prepared from compounds of formula(VII) by process step (iii), which comprises reaction with a suitableaniline or 3-aminopyridine in the presence of a suitable acid, such astrifluoroacetic acid, para-toluenesulfonic acid, camphor sulfonic acid,or hydrochloric acid, in a suitable solvent such as xylene, which isheated at 150° C. Typical conditions comprise heating 1 equivalent of1,2,4-oxadiazole (VII), 3 equivalents of aniline/aminopyridine and0.04-0.1 equivalents of para-toluenesulfonic acid in xylene at 150° C.for 18-22 hours.

Compounds of formula (I) may be prepared from compounds of formula(VIII) by process step (iv), which comprises a Suzuki coupling reactionas described in scheme 1.

Compounds of general formula (I) where R² is NR⁷R⁸ or a 5-7 memberedN-linked heterocycle as described herein, R³ is H and where R¹, R⁴, R⁵,R⁶, R⁷, R⁸, X, V, W, Y and Z are as described herein may be preparedaccording to reaction scheme 3.

Compounds of formula (IX) can be prepared from aryl hydrazides offormula (III) by process step (v), which comprises reaction with asuitable acid chloride, such as chloroacetyl chloride, in the presenceof a base, such as triethylamine, N-methyl morpholine, sodium carbonateor potassium hydroxide. Typical conditions comprise reacting 1.0equivalents of aryl hydrazide (III), 1.0-1.3 equivalents of chloroacetylchloride, 1.2-2.0 equivalents of N-methyl morpholine in dichloromethaneat 25° C.

Compounds of formula (X) can be prepared from compounds of formula (IX)by process step (vi), which comprises reaction with a suitabledehydrating agent such as phosphorous oxychloride,trifluoromethanesulfonic anhydride, or phosphorous pentachloride betweena temperature of 25° C. and 110° C. Typical conditions comprise heating1.0 equivalent of compound (IX) in phosphorous oxychloride at 110° C.for 4 hours.

Compounds of formula (XI) can be prepared from alkyl chlorides offormula (X) by process step (vii), which comprises reaction with asuitable primary or secondary amine (HNR⁷R⁸) or a 5-7 membered N-linkedheterocycle, optionally in the presence of a base such as potassiumcarbonate, sodium carbonate or cesium carbonate, in a suitable solventsuch as acetonitrile or N,N-dimethylformamide, by heating at 25-50° C.for 2-18 hours. Typical conditions comprise reacting 1 equivalent ofalkyl chloride (X), 1.5 equivalent of amine (HNR⁷R⁸) or 5-7 memberedN-linked heterocycle and 2 equivalents of potassium carbonate inacetonitrile for 18 hours at 25° C.

Compounds of formula (XII) may be prepared from compounds of formula(XI) by process step (iii), which comprises reaction with a suitableaniline or 3-aminopyridine, in the presence of a suitable acid, such astrifluoroacetic acid, para-toluenesulfonic acid, camphor sulfonic acid,or hydrochloric acid, in a suitable solvent such as xylene, heated at150° C. Typical conditions comprise heating 1 equivalent of1,2,4-oxadiazole (XI), 3 equivalents of aniline/aminopyridine and0.04-0.1 equivalents of para-toluenesulfonic acid in xylene at 150° C.for 18-24 hours.

Compounds of formula (I) may be prepared from compounds of formula (XII)by process step (iv), which comprises reaction with a suitable boronicacid such as 2,3-dimethylphenyl boronic acid (commercially available),in a suitable solvent, in the presence of a suitable base and palladiumcatalyst as described in scheme 1.

Compounds of general formula (I) where R¹, R², R³, R⁴, R⁵, R⁶, X, V, W,Y and Z are as described herein may alternatively be prepared accordingto reaction scheme 4.

Compounds of formula (II) are prepared as described in scheme 1.

Compounds of general formula (XIII) can be prepared from compounds ofgeneral formula (II) by process step (iv) as described in scheme 1.

Compounds of general formula (XIV) can be prepared from compounds ofgeneral formula (XIII) by process step (i) as described in scheme 1.

When R²=H, compounds of general formula (XV) can be prepared fromcompounds of general formula (XIV) by process step (viii), using amethod analogous to process step (ii), as described in scheme 1.

When R²≠H, compounds of general formula (XV) can be prepared fromcompounds of general formula (XIV) by process step (viii), using methodsanalogous to steps (v) and (vi), as described in scheme 2 or steps (v),(vi) and (vii) as described in scheme 3.

Compounds of general formula (I) can be prepared from compounds ofgeneral formula (XV) by process step (iii), as described in scheme 1.

Compounds of general formula (I) where X is C—R⁶, R³ is H and where R¹,R², R⁴, R⁵, R⁶, V, W, Y and Z are as described herein may alternativelybe prepared according to reaction scheme 5.

Compounds of formula (III) are prepared as described in scheme 1.

When R²=H, compounds of general formula (IV) can be prepared fromcompounds of general formula (III) by process step (viii), using amethod analogous to process step (ii), as described in scheme 1.

When R²≠H, compounds of general formula (IV) can be prepared fromcompounds of general formula (III) by process step (viii), using methodsanalogous to steps (v) and (vi), as described in scheme 2 and steps (v),(vi) and (vii) as described in Scheme 3.

Compounds of general formula (XV) may be prepared from compounds ofgeneral formula (IV) by process step (iv) as described in scheme 1.

Compounds of general formula (I) may be prepared from compounds ofgeneral formula (XV) by process step (iii) as described in scheme 1.

Compounds of general formula (I) and (VIII) where R¹, R², R⁴, R⁵, V, W,X, and Y are described herein and R³═H may be prepared according toreaction

Compounds of formula (I) and (VIII) may be prepared from compounds offormula (XIV) and (III) respectively by process step (ix), whichcomprises sequential reaction with a dimethylacetamide dimethylacetal ina suitable solvent such as tetrahydrofuran or acetic acid heated at55-60° C. followed by reaction with a suitable aniline or aminopyridinein the presence of a suitable acid such as acetic acid heated at 90-100°C. Typical conditions comprise heating 1.0 equivalent of acyl hydrazide,1.5 equivalents of dimethylacetamide dimethylacetal (Aldrich) in THF at55° C. for 2 hours followed by the addition of 1.5 equivalents of2-methoxy-5-aminopyridine (Aldrich) and heating in acetic acid at 90° C.for 5 hours.

All of the above reactions and the preparations of novel startingmaterials disclosed in the preceding methods are conventional andappropriate reagents and reaction conditions for their performance orpreparation as well as procedures for isolating the desired productswill be well-known to those skilled in the art with reference toliterature precedents and the Examples and Preparations hereto.

Utility

The compounds of the invention are useful because they havepharmacological activity in mammals, including humans. Moreparticularly, they are useful in the treatment or prevention of adisorder in which modulation of the levels of oxytocin could provide abeneficial effect. Disease states that may be mentioned include sexualdysfunction, particularly premature ejaculation, preterm labour,complications in labour, appetite and feeding disorders, benignprostatic hyperplasia, premature birth, dysmenorrhoea, congestive heartfailure, arterial hypertension, liver cirrhosis, nephrotic hypertension,ocular hypertension, obsessive compulsive disorder and neuropsychiatricdisorders.

Sexual dysfunction (SD) is a significant clinical problem which canaffect both males and females. The causes of SD may be both organic aswell as psychological. Organic aspects of SD are typically caused byunderlying vascular diseases, such as those associated with hypertensionor diabetes mellitus, by prescription medication and/or by psychiatricdisease such as depression. Physiological factors include fear,performance anxiety and interpersonal conflict. SD impairs sexualperformance, diminishes self-esteem and disrupts personal relationshipsthereby inducing personal distress. In the clinic, SD disorders havebeen divided into female sexual dysfunction (FSD) disorders and malesexual dysfunction (MSD) disorders (Melman et al, J. Urology, 1999, 161,5-11).

FSD can be defined as the difficulty or inability of a woman to findsatisfaction in sexual expression. FSD is a collective term for severaldiverse female sexual disorders (Leiblum, S. R. (1998). Definition andclassification of female sexual disorders. Int. J. Impotence Res., 10,S104-S106; Berman, J. R., Berman, L. & Goldstein, I. (1999). Femalesexual dysfunction: Incidence, pathophysiology, evaluations andtreatment options. Urology, 54, 385-391). The woman may have lack ofdesire, difficulty with arousal or orgasm, pain with intercourse or acombination of these problems. Several types of disease, medications,injuries or psychological problems can cause FSD. Treatments indevelopment are targeted to treat specific subtypes of FSD,predominantly desire and arousal disorders.

The categories of FSD are best defined by contrasting them to the phasesof normal female sexual response: desire, arousal and orgasm (Leiblum,S. R. (1998). Definition and classification of female sexual disorders,Int. J. Impotence Res., 10, S104-S106). Desire or libido is the drivefor sexual expression. Its manifestations often include sexual thoughtseither when in the company of an interested partner or when exposed toother erotic stimuli. Arousal is the vascular response to sexualstimulation, an important component of which is genital engorgement andincludes increased vaginal lubrication, elongation of the vagina andincreased genital sensation/sensitivity. Orgasm is the release of sexualtension that has culminated during arousal.

Hence, FSD occurs when a woman has an inadequate or unsatisfactoryresponse in any of these phases, usually desire, arousal or orgasm. FSDcategories include hypoactive sexual desire disorder, sexual arousaldisorder, orgasmic disorders and sexual pain disorders. Although thecompounds of the invention will improve the genital response to sexualstimulation (as in female sexual arousal disorder), in doing so it mayalso improve the associated pain, distress and discomfort associatedwith intercourse and so treat other female sexual disorders.

Thus, in accordance with a further aspect of the invention, there isprovided the use of a compound of the invention in the preparation of amedicament for the treatment or prophylaxis of hypoactive sexual desiredisorder, sexual arousal disorder, orgasmic disorder and sexual paindisorder, more preferably for the treatment or prophylaxis of sexualarousal disorder, orgasmic disorder, and sexual pain disorder, and mostpreferably in the treatment or prophylaxis of sexual arousal disorder.

Hypoactive sexual desire disorder is present if a woman has no or littledesire to be sexual, and has no or few sexual thoughts or fantasies.This type of FSD can be caused by low testosterone levels, due either tonatural menopause or to surgical menopause. Other causes includeillness, medications, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterised by inadequategenital response to sexual stimulation. The genitalia do not undergo theengorgement that characterises normal sexual arousal. The vaginal wallsare poorly lubricated, so that intercourse is painful. Orgasms may beimpeded. Arousal disorder can be caused by reduced oestrogen atmenopause or after childbirth and during lactation, as well as byillnesses, with vascular components such as diabetes andatherosclerosis. Other causes result from treatment with diuretics,antihistamines, antidepressants eg SSRIs or antihypertensive agents.

Sexual pain disorders (includes dyspareunia and vaginismus) ischaracterised by pain resulting from penetration and may be caused bymedications which reduce lubrication, endometriosis, pelvic inflammatorydisease, inflammatory bowel disease or urinary tract problems.

The prevalence of FSD is difficult to gauge because the term coversseveral types of problem, some of which are difficult to measure, andbecause the interest in treating FSD is relatively recent. Many women'ssexual problems are associated either directly with the female ageingprocess or with chronic illnesses such as diabetes and hypertension.

Because FSD consists of several subtypes that express symptoms inseparate phases of the sexual response cycle, there is not a singletherapy. Current treatment of FSD focuses principally on psychologicalor relationship issues. Treatment of FSD is gradually evolving as moreclinical and basic science studies are dedicated to the investigation ofthis medical problem. Female sexual complaints are not all psychologicalin pathophysiology, especially for those individuals who may have acomponent of vasculogenic dysfunction (eg FSAD) contributing to theoverall female sexual complaint. There are at present no drugs licensedfor the treatment of FSD. Empirical drug therapy includes oestrogenadministration (topically or as hormone replacement therapy), androgensor mood-altering drugs such as buspirone or trazodone. These treatmentoptions are often unsatisfactory due to low efficacy or unacceptableside effects.

The Diagnostic and Statistical Manual (DSM) IV of the AmericanPsychiatric Association defines Female Sexual Arousal Disorder (FSAD) asbeing:

-   -   “a persistent or recurrent inability to attain or to maintain        until completion of the sexual activity adequate        lubrication-swelling response of sexual excitement. The        disturbance must cause marked distress or interpersonal        difficulty.”

The arousal response consists of vasocongestion in the pelvis, vaginallubrication and expansion and swelling of the external genitalia. Thedisturbance causes marked distress and/or interpersonal difficulty.

FSAD is a highly prevalent sexual disorder affecting pre-, peri- andpost menopausal (±HRT) women. It is associated with concomitantdisorders such as depression, cardiovascular diseases, diabetes and UGdisorders.

The primary consequences of FSAD are lack of engorgement/swelling, lackof lubrication and lack of pleasurable genital sensation. The secondaryconsequences of FSAD are reduced sexual desire, pain during intercourseand difficulty in achieving an orgasm.

Male sexual dysfunction (MSD) is generally associated with eithererectile dysfunction, also known as male erectile dysfunction (MED)and/or ejaculatory disorders such as premature ejaculation, anorgasmia(unable to achieve orgasm) or desire disorders such as hypoactive sexualdesire disorder (lack of interest in sex).

PE is a relatively common sexual dysfunction in men. It has been definedin several different ways but the most widely accepted is the Diagnosticand Statistical Manual of Mental Disorders IV one which states:

-   -   “PE is a lifelong persistent or recurrent ejaculation with        minimal sexual stimulation before, upon or shortly after        penetration and before the patient wishes it. The clinician must        take into account factors that affect duration of the excitement        phase, such as age, novelty of the sexual partner or        stimulation, and frequency of sexual activity. The disturbance        causes marked distress of interpersonal difficulty.”

The International Classification of Diseases 10 definition states:

-   -   “There is an inability to delay ejaculation sufficiently to        enjoy lovemaking, manifest as either of the following: (1)        occurrence of ejaculation before or very soon after the        beginning of intercourse (if a time limit is required: before or        within 15 seconds of the beginning of intercourse); (2)        ejaculation occurs in the absence of sufficient erection to make        intercourse possible. The problem is not the result of prolonged        abstinence from sexual activity”

Other definitions which have been used include classification on thefollowing criteria:

-   -   Related to partner's orgasm    -   Duration between penetration and ejaculation    -   Number of thrust and capacity for voluntary control

Psychological factors may be involved in PE, with relationship problems,anxiety, depression, prior sexual failure all playing a role.

Ejaculation is dependent on the sympathetic and parasympathetic nervoussystems. Efferent impulses via the sympathetic nervous system to the vasdeferens and the epididymis produce smooth muscle contraction, movingsperm into the posterior urethra. Similar contractions of the seminalvesicles, prostatic glands and the bulbouretheral glands increase thevolume and fluid content of semen. Expulsion of semen is mediated byefferent impulses originating from a population of lumber spinothalamiccells in the lumbosacral spinal cord (Coolen & Truitt, Science, 2002,297, 1566) which pass via the parasympathetic nervous system and causerhythmic contractions of the bulbocavernous, ischiocavernous and pelvicfloor muscles. Cortical control of ejaculation is still under debate inhumans. In the rat the medial pre-optic area and the paraventricularnucleus of the hypothalamus seem to be involved in ejaculation.

Ejaculation comprises two separate components—emission and ejaculation.Emission is the deposition of seminal fluid and sperm from the distalepididymis, vas deferens, seminal vesicles and prostrate into theprostatic urethra. Subsequent to this deposition is the forcibleexpulsion of the seminal contents from the urethral meatus. Ejaculationis distinct from orgasm, which is purely a cerebral event. Often the twoprocesses are coincidental.

A pulse of oxytocin in peripheral serum accompanies ejaculation inmammals. In man oxytocin but not vasopressin plasma concentrations aresignificantly raised at or around ejaculation. Oxytocin does not induceejaculation itself; this process is 100% under nervous control viaα1-adrenoceptor/sympathetic nerves originating from the lumbar region ofthe spinal cord. The systemic pulse of oxytocin may have a role in theperipheral ejaculatory response. It could serve to modulate thecontraction of ducts and glandular lobules throughout the male genitaltract, thus influencing the fluid volume of different ejaculatecomponents for example. Oxytocin released centrally into the brain couldinfluence sexual behaviour, subjective appreciation of arousal (orgasm)and latency to subsequent ejaculation.

Accordingly, one aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention or treatment of sexual dysfunction,preferably male sexual dysfunction, most preferably prematureejaculation.

It has been demonstrated in the scientific literature that the number ofoxytocin receptors in the uterus increases during pregnancy, mostmarkedly before the onset of labour (Gimpl & Fahrenholz, 2001,Physiological Reviews, 81 (2), 629-683). Without being bound by anytheory it is known that the inhibition of oxytocin can assist inpreventing preterm labour and in resolving complications in labour.

Accordingly, another aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention or treatment of preterm labour andcomplications in labour.

Oxytocin has a role in feeding; it reduces the desire to eat (Arletti etal., Peptides, 1989, 10, 89). By inhibiting oxytocin it is possible toincrease the desire to eat. Accordingly oxytocin inhibitors are usefulin treating appetite and feeding disorders.

Accordingly, a further aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention or treatment of appetite and feedingdisorders.

Oxytocin is implicated as one of the causes of benign prostatichyperplasia (BPH). Analysis of prostate tissue have shown that patientswith BPH have increased levels of oxytocin (Nicholson & Jenkin, Adv.Exp. Med. & Biol., 1995, 395, 529). Oxytocin antagonists can help treatthis condition.

Accordingly, another aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention or treatment of benign prostatichyperplasia.

Oxytocin has a role in the causes of dysmenorrhoea due to its activityas a uterine vasoconstrictor (Akerlund, Ann. NY Acad. Sci., 1994, 734,47). Oxytocin antagonists can have a therapeutic effect on thiscondition.

Accordingly, a further aspect of the invention provides for the use of acompound of formula (I), without the proviso, in the preparation of amedicament for the prevention of treatment of dysmenorrhoea.

It is to be appreciated that all references herein to treatment includecurative, palliative and prophylactic treatment.

The compounds of the present invention may be coadministered with one ormore agents selected from:

-   1) One or more selective serotonin reuptake inhibitors (SSRIs) such    as dapoxetine, paroxetine,    3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzenesulfonamide    (Example 28, WO 0172687),    3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzenesulfonamide    (Example 12, WO 0218333),    N-methyl-N-({3-[3-methyl-4-(methylsulfanyl)phenoxy]-4-pyridinyl}methyl)amine    (Example 38, PCT Application no PCT/IB02/01032).-   2) One or more local anaesthetics;-   3) one or more α-adrenergic receptor antagonists (also known as    α-adrenoceptor blockers, α-receptor blockers or α-blockers);    suitable α₁-adrenergic receptor antagonists include: phentolamine,    prazosin, phentolamine mesylate, trazodone, alfuzosin, indoramin,    naftopidil, tamsulosin, phenoxybenzamine, rauwolfa alkaloids,    Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591,    doxazosin, Example 19 of WO9830560, terazosin and abanoquil;    suitable α₂-adrenergic receptor antagonists include dibenamine,    tolazoline, trimazosin, efaroxan, yohimbine, idazoxan clonidine and    dibenamine; suitable non-selective α-adrenergic receptor antagonists    include dapiprazole; further α-adrenergic receptor antagonists are    described in PCT application WO99/30697 published on 14 Jun. 1998    and U.S. Pat. Nos. 4,188,390; 4,026,894; 3,511,836; 4,315,007;    3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and    2,599,000 each of which is incorporated herein by reference;-   4) one or more cholesterol lowering agents such as statins (e.g.    atorvastatin/Lipitor—trade mark) and fibrates;-   5) one or more of a serotonin receptor agonist, antagonist or    modulator, more particularly agonists, antagonists or modulators for    example 5HT1A, 5HT2A, 5HT2C, 5HT3, 5HT6 and/or 5HT7 receptors,    including those described in WO-09902159, WO-00002550 and/or    WO-00028993;    -   6) one or more NEP inhibitors, preferably wherein said NEP is EC        3.4.24.11 and more preferably wherein said NEP inhibitor is a        selective inhibitor for EC 3.4.24.11, more preferably a        selective NEP inhibitor is a selective inhibitor for EC        3.4.24.11, which has an IC₅₀ of less than 100 nM (e.g.        ompatrilat, sampatrilat) suitable NEP inhibitor compounds are        described in EP-A-1097719; IC50 values against NEP and ACE may        be determined using methods described in published patent        application EP1097719-A1, paragraphs [0368] to [0376];-   7) one or more of an antagonist or modulator for vasopressin    receptors, such as relcovaptan (SR 49059), conivaptan, atosiban,    VPA-985, CL-385004, Vasotocin.-   8) Apomorphine—teachings on the use of apomorphine as a    pharmaceutical may be found in U.S. Pat. No. 5,945,117;-   9) Dopamine agonists (in particular selective D2, selective D3,    selective D4 and selective D2-like agents) such as Pramipexole    (Pharmacia Upjohn compound number PNU95666), ropinirole,    apomorphine, surmanirole, quinelorane, PNU-142774, bromocriptine,    carbergoline, Lisuride;-   10) Melanocortin receptor agonists (e.g. Melanotan II and PT141) and    selective MC3 and MC4 agonists (e.g.THIQ);-   11) Mono amine transport inhibitors, particularly Noradrenaline    Re-uptake Inhibitors (NRIs) (e.g. Reboxetine), other Serotonin    Re-uptake Inhibitors (SRIs) (e.g. paroxetine, dapoxetine) or    Dopamine Re-uptake Inhibitors (DRIs);-   12) 5-HT_(1A) antagonists (e.g. robalzotan); and    -   13) PDE inhibitors such as PDE2 (e.g.        erythro-9-(2-hydroxyl-3-nonyl)-adenine) and Example 100 of EP        0771799-incorporated herein by reference) and in particular a        PDE5 inhibitor such as the pyrazolo[4,3-d]pyrimidin-7-ones        disclosed in EP-A-0463756; the pyrazolo[4,3-d]pyrimidin-7-ones        disclosed in EP-A-0526004; the pyrazolo[4,3-d]pyrimidin-7-ones        disclosed in published international patent application WO        93/06104; the isomeric pyrazolo[3,4-d]pyrimidin-4-ones disclosed        in published international patent application WO 93/07149; the        quinazolin-4-ones disclosed in published international patent        application WO 93/12095; the pyrido[3,2-d]pyrimidin-4-ones        disclosed in published international patent application WO        94/05661; the purin-6-ones disclosed in published international        patent application WO 94/00453; the        pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published        international patent application WO 98/49166; the        pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published        international patent application WO 99/54333; the        pyrazolo[4,3-d]pyrimidin-4-ones disclosed in EP-A-0995751; the        pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published        international patent application WO 00/24745; the        pyrazolo[4,3-d]pyrimidin-4-ones disclosed in EP-A-0995750; the        compounds disclosed in published international application        WO95/19978; the compounds disclosed in published international        application WO 99/24433 and the compounds disclosed in published        international application WO 93/07124; the        pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published        international application WO 01/27112; the        pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published        international application WO 01/27113; the compounds disclosed        in EP-A-1092718 and the compounds disclosed in EP-A-1092719.

Preferred PDE5 inhibitors for use with the invention:

-   5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (sildenafil) also known as    1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine    (see EP-A-0463756);-   5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see EP-A-0526004);-   3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO98/49166);-   3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO99/54333);-   (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    also known as    3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO99/54333);-   5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    also known as    1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine    (see WO 01/27113, Example 8);-   5-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO 01/27113, Example 15);-   5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO 01/27113, Example 66);-   5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO 01/27112, Example 124);-   5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO 01/27112, Example 132);-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione    (IC-351), i.e. the compound of examples 78 and 95 of published    international application WO95/19978, as well as the compound of    examples 1, 3, 7 and 8;-   2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one    (vardenafil) also known as    1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine,    i.e. the compound of examples 20, 19, 337 and 336 of published    international application WO99/24433; and    -   the compound of example 11 of published international        application WO93/07124 (EISAI); and    -   compounds 3 and 14 from Rotella D P, J. Med. Chem., 2000, 43,        1257.

Still further PDE5 inhibitors for use with the invention include:

-   4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone;    1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinozolinyl]-4-piperidine-carboxylic    acid, monosodium salt;    (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one;    furazlocillin;    cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]purin-4-one;    3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;    3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;    4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)    propoxy)-3-(2H)pyridazinone;    1-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;    1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic    acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome);    Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa    Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering Plough);    GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 &    38-9456 (Bayer) and Sch-51866.

The contents of the published patent applications and journal articlesand in particular the general formulae of the therapeutically activecompounds of the claims and exemplified compounds therein areincorporated herein in their entirety by reference thereto.

More preferred PDE5 inhibitors for use with the invention are selectedfrom the group:

-   5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (sildenafil);-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,    1′:6,1]pyrido[3,4-b]indole-1,4-dione (IC-351);-   2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one    (vardenafil); and-   5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    or    5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    and pharmaceutically acceptable salts thereof.

A particularly preferred PDE5 inhibitor is5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil) (also known as1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine)and pharmaceutically acceptable salts thereof. Sildenafil citrate is apreferred salt.

Preferred agents for coadministration with the compounds of the presentinvention are PDE5 inhibitors, selective serotonin reuptake inhibitors(SSRIs), vasopressin V_(1A) antagonists, α-adrenergic receptorantagonists, NEP inhibitors, dopamine agonists and melanocortin receptoragonists as described above. Particularly preferred agents forcoadministration are PDE5 inhibitors, SSRIs, and V_(1A) antagonists asdescribed herein.

Assay

A suitable assay for determining the oxytocin antagonist activity of acompound is detailed herein below.

Oxytocin Receptor Beta-Lactamase Assay

Materials:

Cell Culture/Reagents

A: Cell Culture

Nutrient Mixture

F12 Ham's

Foetal Bovine Serum (FBS)

Geneticin

Zeocin

Trypsin/EDTA

PBS (phosphate buffered saline)

HEPES

B: Reagents

Oxytocin

OT receptor-specific antagonist

Molecular grade Dimethyl Sulphoxide (DMSO)

Trypan Blue Solution 0.4% CCF4-AM (Solution A)

Pluronic F127s (Solution B)

24% PEG, 18% TR40 (Solution C)

Probenecid (Dissolved at 200 mM in 200 mM NaOH, Solution D)

Methods

Cell Culture

Cells used are CHO-OTR/NFAT-β-Lactamase. The NFAT-β-lactamase expressionconstruct was transfected into the CHO-OTR cell line and clonalpopulations were isolated via fluorescence activated cell sorting(FACS). An appropriate clone was selected to develop the assay.

Growth Medium

90% F12 Nutrient Mix, 15 mM HEPES

10% FBS

-   -   400 g/ml Geneticin    -   200 g/ml Zeocin    -   2 mM L-Glutamine        Assay Media        99.5% F12 Nutrient Mix, 15 mM HEPES        0.5% FBS        Recovery of cells—A vial of frozen cells is thawed rapidly in        37° C. water bath and the cell suspension transferred into a        T225 flask with 50 ml of fresh growth medium and then incubated        at 37° C., 5% CO₂ in an incubator until the cells adhered to the        flask Replace media with 50 ml of fresh growth media the        following day.

Culturing cells—CHO-OTR-NFAT-βLactamase cells were grown in growthmedium. Cells were harvested when they reached 80-90% confluenceremoving the medium and washing with pre-warmed PBS. PBS was thenremoved and Trypsin/EDTA added (3 mls for T225 cm² flask) beforeincubating for 5 min in 37° C./5% CO₂ incubator. When cells weredetached, pre-warmed growth media was added (7 mls for T225 cm² flask)and the cells re-suspended and mixed gently by pipetting to achievesingle cell suspension. The cells were split into T225 flask at 1:10(for 3 days growth) and 1:30 (for 5 days growth) ratio in 35 ml growthmedium.

β-Lactamase Assay Method

Day 1

Cell Plate Preparation

Cells grown at 80-90% confluence were harvested and counted. Suspensionsof cells at 2×105 cells/ml in growth medium were prepared and 30 μl ofcells suspension added in 384-well, black clear-bottom plates. A blankplate containing diluents from each reagent was used for backgroundsubtraction.

Plates were incubated at 37° C., 5% CO₂ overnight.

Day 2

Cells Stimulation

-   -   10 μl antagonist/compound (diluted in assay media containing        1.25% DMSO=antagonist diluent) was added to appropriate wells        and incubated for 15 minutes at 37° C., 5% CO₂.    -   10 μl oxytocin, made up in assay media, was added to all wells        and incubated for 4 hours at 37° C., 5% CO₂.    -   A separate 384-well cell plate was used to generate an oxytocin        dose response curve. (10 μl antagonist diluent was added to        every well. 10 μl of oxytocin was then added. The cells are then        treated as per antagonist/compound cell plates).        Preparation of 1 ml of 6× Loading Buffer with Enhanced Loading        Protocol (This Requires Scale-Up According to Number of Plates        to be Screened)    -   12 μl of solution A (1 mM CCF4-AM in Dry DMSO) was added to 60        μl of solution B (100 mg/ml Pluronic-F127 in DMSO+0.1% Acetic        Acid) and vortexed.    -   The resulting solution was added to 925 μl of solution C (24%        w/w PEG400, 18% TR40 v/v in water).    -   75 μl of solution D was added (200 mM probenecid in 200 mM        NaOH).    -   10 μl of 6× Loading Buffer was added to all wells and incubated        for 1.5 hrs-2 hrs at room temperature in the dark.    -   The plates were read using an LJL Analyst, Excitation 405 nm,        Emission 450 nm and 530 nm, gain optimal, lagtime 0.40 μs        integration, 4 flashes, bottom reading.

Using the assay described above, the compounds of the present inventionall exhibit oxytocin antagonist activity, expressed as a Ki value, ofless than 500 nM. Preferred examples have Ki values of less than 200 nMand particularly preferred examples have Ki values of less than 50 nM.

The compound of example 8 has a Ki value of 3 nM.

The invention is illustrated by the following non-limiting examples inwhich the following abbreviations and definitions are used:

Arbocel ® Filtration agent, from J. Rettenmaier & Sohne, Germany APCl+Atmospheric Pressure Chemical Ionisation (positive scan) CDCl₃Chloroform-d1 d Doublet dd Doublet of doublets DMSO DimethylsulfoxideES+ Electrospray ionisation positive scan. eq Equivalent ¹H NMR ProtonNuclear Magnetic Resonance Spectroscopy MS (Low Resolution) MassSpectroscopy m Multiplet m/z Mass spectrum peak q Quartet s Singlet tTriplet δ Chemical shift

Preparation 1bis[2-[(Dimethylamino-κN)methyl]phenyl-κC]bis[μ-(trifluoroacetato-κO:κO′)]-palladium

To a suspension of palladium chloride (3.43 g, 19.4 mmol) in methanol(200 mL) under nitrogen at room temperature was addedN,N-dimethylbenzylamine (5.82 mL, 38.7 mmol) via syringe. The resultingred/brown suspension was stirred at room temperature for 24 hours. Thenow green/brown suspension was concentrated in vacuo to remove methanol,re-dissolved in dichloromethane (150 mL) and passed through a pad ofsilica gel washing through with dichloromethane. The resulting brightyellow filtrate was concentrated in vacuo and recrystallised fromdichloromethane:ether to give the desired product, 4.66 g.

¹HNMR (CDCl₃, 300 MHz) δ: 2.86 (s, 6H), 2.89 (s, 6H), 3.95 (s, 4H),6.84-7.24 (m, 8H)

Preparation 2bis[2-[(Dimethylamino-κN)methyl]phenyl-κC]bis[μ-(trifluoroacetato-κO:κO′)]-palladium

To a solution of silver trifluoroacetate (4.48 g, 20.3 mmol) in acetone(30 mL) under nitrogen at room temperature was added a solution of thecomplex of preparation 1 (5.60 g, 10.15 mmol) in dichloromethane (100mL). A thick white precipitate appeared during addition. The suspensionwas stirred for 15 minutes, and was then filtered through a pad ofsilica gel, washing with dichloromethane. Concentration in vacuo gave abright yellow powder that was recrystallised from dichloromethane:etherto give the desired product, 7.06 g.

¹HNMR (CDCl₃, 300 MHz) δ: 2.05 (s, 6H), 2.88 (s, 6H), 3.18 (d, 2H), 3.63(d, 2H), 6.89-6.97 (m, 6H), 7.00-7.10 (m, 2H)

Preparation 3[2-[(Dimethylamino-κN)methyl]phenyl-κC](tricyclohexylphosphine)(trifluoroacetato-κO-(SP-4-3)-palladium

To a solution of the product of preparation 2 (6.43 g, 9.10 mmol) indichloromethane (50 mL) under nitrogen at room temperature was added asolution of tricyclohexylphosphine (6.89 g, 24.5 mmol) indichloromethane (20 mL). After stirring for 1 hour, the solution waspassed through a plug of silica gel (7 cm×2 cm) washing withdichloromethane (400 mL), and the pale yellow filtrate concentrated invacuo. Recrystallisation from dichloromethane:ether gave the desiredcomplex, 10.53 g.

¹HNMR (CDCl₃, 300 MHz) δ: 1.05-2.30 (m, 33H), 2.57 (s, 3H), 2.58 (s,3H), 3.93 (s, 2H), 6.86-6.98 (m, 3H), 7.10-7.12 (m, 1H)

Preparation 4 2-(4-Bromo-phenyl)-5-methyl-[1,3,4]oxadiazole

4-Bromo-benzoic acid hydrazide (12.90 g, 60 mmol) andN,N-dimethylacetamide dimethyl acetal (12 mL, 82.0 mmol) were dissolvedin N,N-dimethylformamide (100 mL) and the solution heated to 60° C. for2 hours. The solution was concentrated in vacuo and the residue taken upin toluene (80 mL) and treated with para-toluenesulfonic acidmonohydrate (200 mg, 1.50 mmol). The mixture was heated to reflux for 2hours, allowed to cool, and the product crystallised from the solutionand was collected by filtration. The crude product was washed with etherand dried in vacuo to yield a white solid. The filtrate was concentratedin vacuo and the residue combined with the white solid, dissolved intoluene (50 mL) and treated with para-toluenesulfonic acid monohydrate(100 mg, 0.75 mmol). The mixture was heated to reflux for 3 hours,allowed to cool and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with pentane:ethyl acetate80:20 to 40:60 to yield the title product, 12.00 g.

¹HNMR (CDCl₃, 400 MHz) δ: 2.61 (s, 3H), 7.62 (d, 2H), 7.88 (d, 2H). MSES+ m/z 239 [MH]⁺

Preparation 53-(4-Bromo-phenyl)-4-(4-methoxy-phenyl)-5-methyl-4H-[1,2,4]triazole

The product of preparation 4 (5.00 g, 20.9 mmol) was added to a solutionof para-toluenesulfonic acid monohydrate (100 mg, 0.75 mmol) and4-methoxyphenylamine (7.70 g, 62.5 mmol) in xylene (150 mL) and thereaction mixture heated to 150° C. for 22 hours. The reaction mixturewas concentrated in vacuo and the residue taken up in dichloromethaneand purified by column chromatography on silica gel eluting withdichloromethane:methanol:0.88 ammonia 100:0:0 to 97:3:0.3 to yield thetitle product, 7.05 g.

¹HNMR (DMSO-D₆, 400 MHz) δ: 2.20 (s, 3H), 3.81 (s, 3H), 7.07 (m, 2H),7.28 (m, 2H), 7.34 (m, 2H), 7.56 (m, 2H). MS APCl+ m/z 344 [MH]⁺

Preparation 6 5-Bromo-pyridine-2-carboxylic acid hydrazide

5-Bromo-pyridine-2-carboxylic acid methyl ester (J. Org. Chem., 2001,66(2), 605-608, compound 4) (18.10 g, 83 mmol) and hydrazine monohydrate(12.5 mL, 250 mmol) were dissolved in methanol (400 mL) and the reactionmixture heated to reflux for 48 hours. The reaction mixture was thenfiltered and the precipitate collected dried in vacuo to yield the titleproduct, 15.40 g.

¹HNMR (DMSO-D₆, 400 MHz) δ: 4.57 (d, 2H), 7.91 (m, 1H), 8.22 (m, 1H),8.72 (m, 1H), 9.98 (m, 1H). MS ES+ m/z 217 [MH]⁺

Preparation 7 5-Chloro-pyrazine-2-carboxylic acid hydrazide

The title compound was prepared by the method of preparation 6 using5-chloro-pyrazine-2-carboxylic acid methyl ester. 5.01 g, 50% yield ofthe desired product was produced.

¹HNMR (CDCl₃, 400 MHz) δ: 4.09 (d, 2H), 8.52 (s, 1H), 8.66 (bs, 1H),9.14 (s, 1H). Microanalysis: C₅H₅ClN₄O requires: C, 34.80; H, 2.92; N,32.47. found C, 34.89; H, 2.91; N, 32.32. MS APCl+ m/z 173 [MH]⁺

Preparation 8 5-Bromo-pyridine-2-carboxylic acidN′-(2-methoxy-acetyl)-hydrazide

The product of preparation 6 (2.0 g, 9.3 mmol) and N-methylmorpholine(1.3 mL, 12.0 mmol) were dissolved in dichloromethane (60 mL) and thesolution treated with methoxyacetyl chloride (868 μL, 9.50 mmol). Thereaction mixture was stirred at room temperature for 5 hours and thenwashed with water and concentrated in vacuo to afford 2.41 g, 90% yieldof the title product.

¹HNMR (CDCl₃, 400 MHz) δ: 3.46 (s, 3H), 4.07 (s, 2H), 7.98 (dd, 1H),8.02 (dd, 1H), 8.61 (d, 1H), 8.89 (d, 1H), 9.95 (d, 1H). MS ES+ m/z 289[MH]⁺

Preparation 9 6-Chloro-nicotinic acid N′-(2-methoxy-acetyl)-hydrazide

The title product was prepared by the method of preparation 8 using6-chloronicotinic acid hydrazide. 19.0 g, 90% yield of the desiredproduct was produced.

¹HNMR (CDCl₃, 400 MHz) δ: 3.36 (s, 3H), 3.97 (s, 2H), 7.68 (d, 1H), 8.26(dd, 1H), 8.84 (s, 1H), 9.99 (s, 1H), 10.61 (s, 1H). MS ES+ m/z 246[MH]⁺

Preparation 10 5-Chloro-pyrazine-2-carboxylic acidN′-(2-methoxy-acetyl)-hydrazide

The title product was prepared by the method of preparation 8 using thehydrazide of preparation 7. 3.90 g 70% yield of the desired product wasproduced.

MS APCl+ m/z 245 [MH]⁺

Preparation 11 5-Chloro-pyrazine-2-carboxylic acid N′-acetyl-hydrazide

The title product was prepared by the method of preparation 8 using thehydrazide of preparation 7 and acetyl chloride. 4.0 g, 64% of thedesired product was produced.

MS APCl+ m/z 215 [MH]⁺

Preparation 12 5-Bromo-pyridine-2-carboxylic acidN′-(2-chloro-acetyl)-hydrazide

The title product was prepared by the method of preparation 8 using thehydrazide of preparation 6 and chloroacetyl chloride. 4.30 g, 59% yieldof the desired product was produced.

¹HNMR (CDCl₃, 400 MHz) δ: 4.20 (s, 2H), 8.00 (d, 1H), 8.30 (d, 1H), 8.80(s, 1H), 10.40 (s, 1H), 10.70 (s, 1H). MS APCl+ m/z 293 [MH]⁺

Preparation 135-Bromo-2-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyridine

The product of preparation 8 (2.41 g, 8.4 mmol) and phosphorousoxychloride (7 mL) were combined and heated to 110° C. for 4 hours. Thereaction mixture was concentrated in vacuo and the residue taken up inethyl acetate and water. The mixture was neutralised by the addition of10% sodium carbonate solution and the phases separated. The aqueousphase was extracted with ethyl acetate and the combined organics driedover magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel eluting with ethylacetate to yield the title product, 1.01 g, 45% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 3.48 (s, 3H), 4.73 (s, 2H), 8.01 (dd, 1H),8.12 (dd, 1H), 8.81 (dd, 1H). MS APCl+ m/z 272 [MH]⁺

Preparation 142-Chloro-5-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyridine

The title compound was prepared by the method of preparation 13 usingthe product of preparation 9 provide 7.93 g, 40% yield of title compoundas a rust brown solid.

¹HNMR (CDCl₃, 400 MHz) δ: 3.52 (s, 3H), 4.74 (s, 2H), 7.50 (d, 1H), 8.32(dd, 1H), 9.06 (d, 1H). Microanalysis: C₉H₈ClN₃O₂ requires: C, 47.91; H,3.57; N, 18.62. found C, 47.75; H, 3.50; N, 18.46. MS APCl+ m/z 226[MH]⁺.

Preparation 152-Chloro-5-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyrazine

The title compound was prepared by the method of preparation 13 usingthe product of preparation 10. 1.38 g, 38% yield of the desired productwas produced as a light brown solid.

¹HNMR (CDCl₃, 400 MHz) δ: 3.52 (s, 3H), 4.78 (s, 2H), 8.75 (s, 1H), 9.25(s, 1H) MS APCl+ m/z 227 [MH]⁺

Preparation 16 2-Chloro-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrazine

The title compound was prepared by the method of preparation 13 usingthe product of preparation 11. 30 g, 35% of the desired product wasproduced as a brown solid.

¹HNMR (CDCl₃, 400 MHz) δ: 2.68 (s, 3H), 8.71 (s, 1H), 9.22 (s, 1H) MSAPCl+ m/z 197 [MH]⁺

Preparation 17 5-Bromo-2-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)-pyridine

The title compound was prepared by the method of preparation 13 usingthe product of preparation 12. 2.3 g 57% yield of desired product, wasobtained as an off white solid.

¹HNMR (DMSO-D₆, 400 MHz) δ: 4.80 (s, 2H), 8.05 (d, 1H), 8.15 (d, 1H),8.85 (s, 1H). MS APCl+ m/z 276 [MH]⁺

Preparation 185-Bromo-2-[5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine

The product of preparation 13 (1.01 g, 3.74 mmol),5-amino-2-methoxypyridine (1.40 g, 11.3 mmol) and para-toluenesulfonicacid monohydrate (50 mg, 0.37 mmol) were dissolved in xylene (25 mL) andthe reaction mixture heated to 150° C. for 23 hours. The reactionmixture was concentrated in vacuo and the residue purified by columnchromatography on silica gel eluting with dichloromethane:methanol 100:0to 90:10 to yield the title product, 1.0 g, 72% yield as a purple gum.

¹HNMR (CDCl₃, 400 MHz) δ: 3.32 (s, 3H), 3.99 (s, 3H), 4.46 (s, 2H), 6.82(d, 1H), 7.54 (dd, 1H), 7.90 (dd, 1H), 8.05 (d, 1H), 8.13 (d, 1H), 8.37(d, 1H). MS ES+ m/z 398 [MH]⁺

Preparation 192-(4-Fluoro-2-methyl-phenyl)-5-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyridine

The chloro compound of preparation 14 (500 mg, 2.22 mmol),4-fluoro-2-methylphenyl boronic acid (361 mg, 2.65 mmol), the palladiumcomplex of preparation 3 (10 mg, cat.) and caesium carbonate (2.16 g,6.66 mmol) were dissolved in 1,4-dioxan (10 mL) and the reaction mixtureheated to reflux for 2 hours. Additional palladium complex (10 mg) wasadded and the reaction mixture refluxed for a further 1 hour. Thereaction mixture was concentrated in vacuo and the residue taken up inethyl acetate and water. The phases were separated and the ethyl acetatephase washed with brine, dried over magnesium sulfate and concentratedin vacuo to yield the title product, 690 mg in quantitative yield.

MS APCl+ m/z 300 [MH]⁺

Preparation 202-(2,3-Dimethyl-phenyl)-5-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyridine

The title product was prepared by the method of preparation 19 using2,3-dimethylphenyl boronic acid (399 mg, 1.2 eq) and the product ofpreparation 14 (500 mg, 2.22 mmol). 712 mg, quantitative yield, of thedesired product was produced.

MS APCl+ m/z 296 [MH]⁺

Preparation 212-(2,3-Dimethyl-phenyl)-5-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyrazine

The title product was prepared by the method of preparation 19 using2,3-dimethylphenyl boronic acid and the chloro compound of preparation15. 466 mg, quantitative yield, of the desired product was produced.

¹HNMR (CDCl₃, 400 MHz) δ: 2.29 (s, 3H), 2.39 (s, 3H), 3.52 (s, 3H), 4.78(s, 2H), 7.23-7.37 (m, 3H), 8.84 (s, 1H), 9.54 (s, 1H) MS APCl+ m/z297[MH]⁺

Preparation 222-(4-Fluoro-2-methyl-phenyl)-5-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyrazine

The title product was prepared by the method of preparation 19 using4-fluoro-2-methyl-phenyl boronic acid and the chloro compound ofpreparation 15. 450 mg, 97% of the desired product was produced.

MS APCl+ m/z 301 [MH]⁺

Preparation 232-(2,3-Dimethyl-phenyl)-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrazine

The title product was prepared by the method of preparation 19 using2,3-dimethylphenyl boronic acid and the chloro compound of preparation16. 404 mg, quantitative yield, of the desired product was produced.

MS APCl+ m/z 267 [MH]⁺

Preparation 242-(4-Fluoro-2-methyl-phenyl)-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrazine

The title product was prepared by the method of preparation 19 using4-fluoro-2-methyl-phenyl boronic acid and the chloro compound ofpreparation 16. 377 mg, quantitative yield, of the desired product wasproduced.

MS APCl+ m/z 271 [MH]⁺

Preparation 251-[5-(5-Bromo-pyridin-2-yl)-[1,3,4]oxadiazol-2-ylmethyl]-pyrrolidine-(2S)-2-carboxylicacid amide

The chloro compound of preparation 17 (500 mg, 1.82 mmol) and(S)-prolinamide (312 mg, 2.73 mmol) were dissolved in acetonitrile (10mL) and the mixture treated with potassium carbonate (503 mg, 3.64mmol). The reaction mixture was stirred at room temperature for 18 hoursand then at 50° C. for 2 hours. The reaction mixture was concentrated invacuo and the residue partitioned between ethyl acetate and water. Theprecipitate formed was filtered off and the organic layer of thefiltrate washed with water, 1M sodium hydroxide solution and brine. Theorganic layer was then concentrated in vacuo to yield the title product,540 mg, 84% yield.

¹HNMR (DMSO-D₆, 400 MHz) δ: 1.70 (m, 3H), 2.00 (m, 1H), 2.60 (m, 1H),3.10 (m, 1H), 3.20 (m, 1H), 4.00 (d, 1H), 4.20 (d, 1H), 7.00-7.20 (d,2H), 8.10 (d, 1H), 8.30 (d, 1H), 8.90 (s, 1H).

Preparation 265-Bromo-2-(5-pyrrolidin-1-ylmethyl-[1,3,4]oxadiazol-2-yl)-pyridine

Pyrrolidine (324 mg, 0.38 mL, 4.56 mmol) was added to a stirred solutionof the chloro compound of preparation 17 (500 mg, 1.82 mmol) inacetonitrile (15 mL) at room temperature. After stirring for 18 hoursthe reaction mixture was concentrated in vacuo and the residue taken upin ethyl acetate (50 mL) and washed with 2M aqueous sodium hydroxide,followed by water followed by brine. The organic phase was dried oversodium sulfate, filtered and concentrated in vacuo to afford 407 mg, 72%yield of the title compound.

¹HNMR (CDCl₃, 400 MHz) δ: 1.90 (m, 4H), 2.70 (m, 4H), 4.00 (s, 2H), 8.00(d, 1H), 8.20 (d, 1H), 8.80 (s, 1H).

Preparation 271-[5-(5-Bromo-pyridin-2-yl)-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-ylmethyl]-pyrrolidine-(2S)-2-carboxylicacid amide

The product of preparation 25 (500 mg, 1.20 mmol) and5-amino-2-methoxypyridine (224 mg, 1.81 mmol) were dissolved in xylene(15 mL) and the solution treated with catalytic para-toluenesulfonicacid monohydrate and heated to reflux for 18 hours. The reaction mixturewas concentrated in vacuo and the residue taken up in ethyl acetate andwashed with water, 2M citric acid solution, 2M sodium hydroxidesolution, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel eluting withdichloromethane:methanol 100:0 to 95:5 to yield the title product, 252mg, 46% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 1.80 (m, 2H), 2.20 (m, 1H), 2.60 (m, 1H), 3.10(m, 1H), 3.20 (m, 1H), 3.90 (m, 2H), 4.00 (s, 3H), 5.00 (s, 1H), 6.70(s, 1H), 6.90 (d, 1H), 7.90 (d, 1H), 8.05 (d, 1H), 8.20 (d, 1H), 8.40(s, 1H). MS ES+ m/z 458 [MH]⁺

Preparation 285-Bromo-2-(((5-pyrrolidin-1-ylmethyl)-4-(6-methoxypyridin-3-yl))-4H-[1,2,4]triazol-3-yl)-pyridine

412 mg, 77% yield of the title compound was prepared by the method ofpreparation 27 using the product of preparation 26.

MS ES+ m/z 417 [MH]⁺

Preparation 293-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile

Palladium (II) acetate (224 mg, 5 mol %), potassium acetate (3.68 g,61.2 mmol) and bis(pinacolato)diboron (5.4 g, 21.4 mmol) were added to asolution of 1-bromo-4-cyano-2-methylbenzene (4.0 g, 20.4 mmol) inN,N-dimethylformamide (40 mL) and heated at 80° C. for 18 hours. Aftersuch time the mixture was cooled and filtered through a pad of Celite®,washing with ethyl acetate and water. The organic phase was separated,dried over sodium sulfate and concentrated in vacuo to afford a brownsolid. The solid was purified by trituration in pentane, filtration anddrying to afford the title compound as a beige solid (2.68 g, 54%yield).

¹HNMR (CDCl₃, 400 MHz) δ: 1.35 (s, 12H), 2.55 (s, 3H), 7.41-7.45 (m,2H), 7.82 (d, 1H). MS APCl+ m/z 261 [MNH₄]⁺

Preparation 302-Chloro-5-[4-(6-methoxy-pyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine

The title product was prepared by the method of preparation 18 using theoxadiazole compound of preparation 16 and 5-amino-2-methoxypyridine. 4.3g, 44% yield of the desired product was produced as a beige solid.

¹HNMR (CDCl₃, 400 MHz) δ: 2.36 (s, 3H), 3.99 (s, 3H), 6.86 (d, 1H), 7.45(dd, 1H), 8.02 (d, 1H), 8.27 (d, 1H), 9.23 (d, 1H).

Preparation 312-Chloro-5-[5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine

The title product was prepared by the method of preparation 18 using theoxadiazole compound of preparation 15 and 5-amino-2-methoxypyridine.10.5 g, 59% yield of the desired product was produced as a beige solid.

¹HNMR (CDCl₃, 400 MHz) δ: 3.33 (s, 3H), 3.99 (s, 3H), 4.47 (s, 2H), 6.83(d, 1H), 7.53 (dd, 1H), 8.06 (d, 1H), 8.30 (d, 1H), 9.25 (d, 1H). MSAPCl+ m/z 333 [MH]⁺

Preparation 322-(5-Fluoro-2-methoxy-phenyl)-5-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyridine

The title product was prepared by the method of preparation 19 using5-fluoro-2-methoxy-phenyl boronic acid (565 mg, 3.33 mol) and the chlorocompound from preparation 14 (500 mg, 2.22 mmol). 669 mg, 96% yield ofthe desired product was produced.

¹HNMR (CDCl₃, 400 MHz) δ: 3.51 (s, 3H), 3.88 (s, 3H), 4.75 (s, 2H), 6.97(d, 1H), 7.11 (m, 1H), 7.70 (dd, 1H), 8.11 (d, 1H), 8.37 (dd, 1H), 9.34(d, 1H). MS APCl+ m/z 316 [MH]⁺

Preparation 33 6-Chloro-nicotinic acid N′-(2-chloro-acetyl)-hydrazide

Chloroacetyl chloride (2.8 mL, 34.9 mmol) was added dropwise to anice-cooled solution of 6-chloronicotinic acid hydrazide (5 g, 29.1 mmol)and 4-methylmorpholine (4.8 mL, 43.7 mmol) in dichloromethane (100 mL)and the reaction was stirred at room temperature for 3 hours. Theresulting precipitate was then filtered off, slurried withdichloromethane, re-filtered, washed with dichloromethane (×3) and driedto afford the title compound as a beige solid in 57% yield, 4.1 g

¹HNMR (DMSO-D₆, 400 MHz) δ: 4.20 (s, 2H), 7.68 (d, 1H), 8.23 (d, 1H),8.84 (m, 1H), 10.50 (s, 1H), 10.83 (s, 1H). MS APCl+ m/z 248/250 [MH]⁺

Preparation 34 5-Chloro-pyrazine-2-carboxylic acidN′-(2-chloro-acetyl)-hydrazide

The title product was prepared from the product of preparation 7 andchloroacetylchloride, using the method of preparation 33, as a solid in37% yield.

MS APCl+ m/z 249/251 [MH]⁺

Preparation 35 6-Chloro-nicotinic acid N′-acetyl-hydrazide

The title compound was prepared from 6-chloronicotinic acid hydrazideand acetyl chloride, using the method of preparation 33, as a whitesolid in 64% yield.

¹HNMR (DMSO-D₆, 400 MHz) δ: 1.91 (s, 3H), 7.68 (d, 1H), 8.24 (dd, 1H),8.82 (d, 1H), 10.00 (s, 1H), 10.58 (s, 1H). MS APCl+ m/z 214 [MH]⁺

Preparation 36 6-Chloro-nicotinic acidN′-[2-(2-methoxy-ethoxy)-acetyl]-hydrazide

(2-Methoxy-ethoxy)-acetyl chloride (2.13 g, 13.99 mmol) was added to anice-cold solution of 6-chloronicotinic acid hydrazide (2 g, 11.66 mmol)and N-methylmorpholine (1.92 mL, 17.49 mmol) in dichloromethane (60 mL)and the mixture was stirred at room temperature for 18 hours. Themixture was then treated with sodium hydrogen carbonate solution andconcentrated in vacuo. The aqueous residue was extracted withdichloromethane (×2) and the combined organic solutions were washed withbrine and dried over sodium sulfate and concentrated in vacuo to give apale yellow residue. The residue was then stirred in diethyl ether for 2hours, filtered and dried to afford the title compound as a pale yellowsolid in 51% yield, 1.7 g.

¹HNMR (CDCl₃, 400 MHz) δ: 3.46 (s, 3H), 3.62 (m, 2H), 3.78 (m, 2H), 4.21(s, 2H), 7.42 (d, 1H), 8.07 (dd, 1H), 8.82 (d, 1H) 9.28 (brs, 1H), 9.83(brs, 1H). MS APCl+ m/z 288 [MH]⁺

Preparation 37 6-Chloro-nicotinic acid N′-(2-ethoxy-acetyl)-hydrazide

(2-Ethoxy)-acetyl chloride [(1.72 g, 13.99 mmol), Tett. Lett., 35, (39),7269; 1994)] was added to an ice-cold solution of 6-chloronicotinic acidhydrazide (2 g, 11.66 mmol) and N-methylmorpholine (1.92 mL, 17.49 mmol)in dichloromethane (60 mL) and the mixture was stirred at roomtemperature for 18 hours. The mixture was then washed with citric acid,sodium hydrogen carbonate solution and brine and the solvent wasevaporated under reduced pressure to yield some title product as a whitesolid, 880 mg. The combined aqueous washings were extracted with ethylacetate (×2) and the combined organic solutions were dried over sodiumsulfate and concentrated in vacuo to afford a further crop of titlecompound as a pale yellow solid, 1.6 g (total yield of 83%).

¹HNMR (CDCl₃, 400 MHz) δ: 1.21 (t, 3H), 3.55 (q, 2H), 4.06 (s, 2H), 7.38(d, 1H), 8.00 (dd, 1H), 8.77 (d, 1H) 8.99 (brs, 1H), 9.15 (brs, 1H). MSAPCl+ m/z 258/260 [MH]⁺

Preparations 38 to 42

The following compounds, of the general formula shown below, wereprepared by the method of preparation 13 using the appropriate hydrazide(preparations 33-37) and phosphorus oxychloride.

No. R² Y Data Yield 38 Cl CH ¹HNMR(CDCl₃, 400 MHz) δ: 4.80(s, 55% 2H),7.52(d, 1H), 8.35(dd, 1H), 9.08(d, 1H). MS APCl+ m/z 230/232 [MH]⁺ 39 ClN ¹HNMR(CDCl₃, 400 MHz) δ: 4.83(s, 38% 2H), 8.76(s, 1H), 9.36(s, 1H). MSAPCl+ m/z 231/233 [MH]⁺ 40 H CH ¹HNMR(CDCl₃, 400 MHz) δ: 2.66(s, 77%3H), 7.51(d, 1H), 8.31(d, 1H), 9.02(s, 1H). Microanalysis: C₈H₆ClN₃O0.25 H₂O requires: C 48.02; H 3.27; N 21.00; found C 47.89; H 3.23, N20.95. 41

CH ¹HNMR(CDCl₃, 400 MHz) δ: 3.39(s, 3H), 3.59-3.61(m, 2H), 3.78-3.80(m,2H), 4.86(5, 2H), 7.52(d, 1H), 8.33(dd, 1H), 9.07(d, 1H). MS APCl+ m/z270/272 [MH]⁺ 68% 42

CH ¹HNMR(CDCl₃, 400 MHz) δ: 1.28(t, 3H), 3.69(q, 2H), 4.77(s, 2H),7.49(d, 1H), 8.34(dd, 1H), 9.07(d, 1H). MS ES+ m/z 262 [MNa]⁺ 75%

Preparation 42 was purified by column chromatography on silica gel,eluting with pentane:ethyl acetate, 100:0 to 90:10.

Preparation 432-Chloro-5-(5-[1,2,3]triazol-2-ylmethyl-[1,3,4]oxadiazol-2-yl)-pyridine

1H-1,2,3-Triazole (264 mg, 3.85 mmol) was added to a suspension of thechloro compound of preparation 38 (800 mg, 3.5 mmol), and potassiumcarbonate (1.4 g, 7 mmol) in N,N-dimethylformamide (15 mL) and themixture stirred at room temperature for 18 hours. The reaction mixturewas then partitioned between ethyl acetate and water and the organiclayer was separated, washed with brine, dried over sodium sulfate andconcentrated in vacuo to afford the title compound as a yellow solid in71% yield, 650 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 6.08 (s, 2H), 7.66 (d, 1H), 7.80 (s, 2H), 8.38(dd, 1H), 8.99 (d, 1H). MS APCl+ m/z 263 [MH]⁺

Preparations 44 to 45

The following compounds, of the general formula shown below, wereprepared from the product of preparations 38 and 39 using the method ofpreparation 43.

No. R² Y Data Yield 44

N MS APCl+ m/z 264 [MH]⁺ 40% 45

CH ¹HNMR(CDCl₃, 400 MHz) δ: 2.34(s, 6H), 3.78(s, 2H), 7.43(d, 1H),8.28(dd, 1H), 9.01(d, 1H). MS APCl+ m/z 239/241 [MH]⁺ 82%

Preparations 46 to 52

The following compounds, of the general formula shown below, wereprepared by the method of preparation 18 using the appropriateoxadiazole (preparations 14 and 40-45) and 5-amino-2-methoxypyridine.

No. R² Y Data Yield 46

CH ¹HNMR(CDCl₃, 400 MHz) δ: 3.97(s, 3H), 5.75(s, 2H), 6.78(d, 1H),7.24(d, 1H), 7.34(d, 1H), 7.56(s, 2H), 7.90(dd, 1H), 7.94(m, 1H),8.30(d, 1H) MS APCl+ m/z 369 [MH]⁺ 25% 47

N MS APCl+ m/z 370 [MH]⁺ 29% 48

CH ¹HNMR(CDCl₃, 400 MHz) δ: 2.25(s, 6H), 3.46(s, 2H), 3.99(s, 3H),6.85(d, 1H), 7.34(d, 1H), 7.60(dd, 1H), 7.88(dd, 1H), 8.10(d, 1H),8.34(d, 1H) MS APCl+ m/z 345/347 [MH]⁺ 36% 49 OCH₃ CH ¹HNMR(CDCl₃, 400MHz) δ: 3.35(s, 50% 3H), 3.99(s, 3H), 4.48(s, 2H), 6.88(d, 1H), 7.34(d,1H), 7.50(m, 1H), 7.88(m, 1H), 8.10(d, 1H), 8.35(m, 1H) MS APCl+ m/z 332[MH]⁺ 50 H CH ¹HNMR(CDCl₃, 400 MHz) δ: 2.38(s, 33% 3H), 4.00(s, 3H),6.90(d, 1H), 7.35(d, 1H), 7.40(dd, 1H), 7.88(dd, 1H), 8.06(d, 1H),8.31(d, 1H) MS APCl+ m/z 302/304 [MH]⁺ 51

CH ¹HNMR(CDCl₃, 400 MHz) δ: 3.33(s, 3H), 3.48(m, 2H), 3.64(m, 2H),3.99(s, 3H), 4.60(s, 2H), 6.86(d, 1H), 7.35(d, 1H), 7.60(dd, 1H),7.88(dd, 1H), 8.09(d, 1H), 8.35(d, 1H). MS APCl+ m/z 376/378 [MH]⁺ 62%52

CH ¹HNMR(CDCl₃, 400 MHz) δ: 1.14(t, 3H), 3.50(q, 2H), 4.00(s, 3H),4.52(s, 2H), 6.86(d, 1H), 7.34(d, 1H), 7.51(dd, 1H), 7.90(dd, 1H),8.11(d, 1H), 8.36(d, 1H). MS APCl+ m/z 346 [MH]⁺

Preparation 46 was purified by column chromatography on silica gel,eluting with ethyl acetate:pentane, 25:75 to 50:50 to 75:25.

Preparation 48 was purified by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 99:1:0.1 to97:3:0.1, followed by trituration with diethyl ether.

Preparation 49 was purified by column chromatography on silica gel,eluting with ethyl acetate:pentane, 10:90 to 100:0, followed bytrituration with diethyl ether.

Preparation 50 was purified by re-crystallisation from ethyl acetate.

Preparation 51 was purified by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 99:1:0.1.

Preparation 53 4-Bromo-2,3-dimethyl-pyridine 1-oxide

A mixture of 2,3-dimethyl-4-nitropyridine N-oxide (5 g, 29.7 mmol) andhydrogen bromide (30% wt in acetic acid, 100 mL) was heated for 48 hoursat 100° C. The mixture was then filtered, washing through with 2M sodiumhydroxide and the filtrate was extracted with dichloromethane (×3). Thecombined organic solutions were washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by columnchromatography on silica gel, eluting with ethyl acetate:pentane, 50:50,to afford the title product as a pale yellow solid.

¹HNMR (CDCl₃, 400 MHz) δ: 2.44 (s, 3H), 2.58 (s, 3H), 7.30 (d, 1H), 8.01(d, 1H) MS APCl+ m/z 202/204 [MH]⁺

Preparation 54 4-(2,3-Dimethyl-1-oxy-pyridin-4-yl)-benzoic acid methylester

A mixture of the product of preparation 53 (765 mg, 3.78 mmol),4-methoxycarbonylphenylboronic acid (750 mg, 4.16 mmol), caesiumcarbonate (3.7 g, 11.34 mmol) and the product of preparation 3 (50 mg,cat.) in 1,4-dioxan (20 mL) was heated at 110° C. for 3 hours. Themixture was then partitioned between ethyl acetate and water and theaqueous layer was separated and extracted by dichloromethane (×3). Thecombined organic solutions were washed with brine, dried over sodiumsulfate and concentrated in vacuo to give a dark yellow solid. Thissolid was triturated with diethyl ether to afford the title compound asa pale brown solid in 87% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 2.24 (s, 3H), 2.60 (s, 3H), 3.95 (s, 3H), 7.02(d, 1H), 7.35 (m, 2H), 8.12 (m, 2H), 8.22 (d, 1H). MS APCl+ m/z 258 [MH]

Preparation 55 4-(2,3-Dimethyl-1-oxy-pyridin-4-yl)-benzoic acidhydrazide

A mixture of the product of preparation 54 (850 mg, 3.3 mmol) andhydrazine monohydrate (482 μL, 9.9 mmol) in methanol (15 mL) was heatedunder reflux for 3 hours. A further amount of hydrazine monohydrate (482μL, 9.9 mmol) was then added to the reaction mixture and heatingcontinued for 18 hours. The mixture was then filtered through Celite®,washing through with methanol and the filtrate was concentrated in vacuoto give a white solid. The solid was slurried in ethyl acetate, filteredoff, washed with diethyl ether (×2) and vacuum dried to afford the titlecompound as a white solid in 94% yield, 800 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.18 (s, 3H), 2.41 (s, 3H), 4.58 (m, 2H), 7.14(d, 1H), 7.42 (d, 2H), 7.96 (d, 2H), 8.18 (d, 1H), 9.85 (s, 1H). MSAPCl+ m/z 258 [MH]⁺

Preparation 56 1,1,1,2-Tetramethoxy-ethane

Methoxyacetonitrile (50.0 g, 704 mmol) was dissolved in a mixture ofmethanol (34 mL) and diethyl ether (210 mL) and the mixture cooled to00° C. Hydrogen chloride gas was bubbled through the solution for 20minutes and the reaction mixture was stirred at room temperature for 2hours. Hydrogen chloride gas was then bubbled through the mixture for asecond time and it was allowed to stand at room temperature for 18hours. The mixture was filtered and the resulting white solid was washedwith diethyl ether, dissolved in methanol (340 mL) and stirred for 90minutes. The solution was then diluted with ether (370 mL), heated underreflux for 6 hours and left to stand at room temperature for 18 hours.Additional ether (200 mL) was added and the mixture was filtered off.The filtrate was washed with 10% sodium carbonate solution, dried overmagnesium sulfate and concentrated in vacuo to yield the title product,34.5 g.

¹HNMR (CDCl₃, 400 MHz) δ: 3.29 (s, 9H), 3.39 (s, 3H), 3.50 (s, 2H)

Preparation 574-[4-(5-Methoxymethyl-[1,3,4]oxadiazol-2-yl)-phenyl]-2,3-dimethyl-pyridine1-oxide

para-Toluenesulfonic acid (20 mg, cat.) was added to a mixture of theproducts of preparations 55 (400 mg, 1.56 mmol) and 56 (470 mg, 3.12mmol) in methanol (8 mL) and the mixture was heated under reflux for 10hours. The mixture was then treated with sodium hydrogen carbonatesolution and the aqueous mixture was extracted with ethyl acetate (×3).The combined organic solutions were washed with brine, dried over sodiumsulfate and concentrated in vacuo to afford the title product as ayellow oil in 25% yield, 122 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.25 (s, 3H), 2.62 (s, 3H), 3.52 (s, 3H), 4.70(s, 2H), 7.04 (d, 1H), 7.41 (d, 2H), 8.16 (d, 2H), 8.25 (d, 1H). MSAPCl+ m/z 312 [MH]⁺

Preparation 58 6-Chloro-pyridazine-3-carboxylic acid methyl ester

Oxalyl chloride (1.14 mL, 13.09 mmol), was added dropwise to an ice-coldsuspension of 6-chloro-pyridazine-3-carboxylic acid [(1.9 g, 11.9 mmol),J. Het. Chem. 29(6), 1583-92; 1992] in a mixture of dichloromethane (50mL) and N,N-dimethylformamide (1 drop) and the mixture was stirred for 1hour at room temperature. The reaction mixture was then evaporated underreduced pressure and the residue was diluted with dichloromethane (30mL) and cooled to 0° C. Methanol (485 μL, 11.9 mmol) was added and themixture was stirred at 0° C. for 1 hour. Sodium hydrogen carbonatesolution was then added to the reaction mixture and the aqueous layerwas separated and extracted with dichloromethane (×2). The combinedorganic solutions were washed with brine, dried over sodium sulfate andconcentrated in vacuo to afford the title compound as a white solid in65% yield, 1.33 g.

¹HNMR (CDCl₃, 400 MHz) δ: 4.09 (s, 3H), 7.67 (d, 1H), 8.16 (d, 1H). MSAPCl+ m/z 173 [MH]⁺

Preparation 59 6-(4-Fluoro-2-methyl-phenyl)-pyridazine-3-carboxylic acidmethyl ester

The title compound was prepared from the product of preparation 58 and4-fluoro-2-methylphenyl boronic acid, using the method of preparation54. Purification of the crude product by column chromatography on silicagel, eluting with pentane:ethyl acetate:methanol, 75:25:1 to 50:50:1afforded the desired product as a beige solid in 16% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 2.44 (s, 3H), 4.11 (s, 3H), 7.06 (m, 2H), 7.47(dd, 1H), 7.71 (d, 1H), 8.26 (d, 1H). MS APCl+ m/z 247 [MH]⁺

Preparation 60 6-(4-Fluoro-2-methyl-phenyl)-pyridazine-3-carboxylic acidhydrazide

Hydrazine monohydrate (69 μL, 1.42 mmol) was added to a suspension ofthe product of preparation 59 (290 mg, 1.18 mmol) in methanol (5 mL) andthe mixture was stirred for 18 hours at room temperature. The resultingprecipitate was filtered off and dried to afford the title compound as apeach solid in 83% yield, 240 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.42 (s, 3H), 4.18 (brs, 2H), 7.06 (m, 2H),7.46 (dd, 1H), 7.75 (d, 1H), 8.33 (d, 1H), 9.18 (brs, 1H). MS APCl+ m/z247 [MH]

Preparation 61 6-(4-Fluoro-2-methyl-phenyl)-pyridazine-3-carboxylic acidN′-(2-methoxy-acetyl)-hydrazide

The title compound was prepared from the product of preparation 60 andmethoxyacetyl chloride, using the method of preparation 8, as a beigefoam in 95% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 2.43 (s, 3H), 3.52 (s, 3H), 4.14 (s, 2H), 7.06(m, 2H), 7.46 (m, 1H), 7.76 (d, 1H), 8.33 (d, 1H), 8.80 (brs, 1H), 10.06(brs, 1H). MS APCl+ m/z 319 [MH]⁺

Preparation 623-(4-Fluoro-2-methyl-phenyl)-6-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyridazine

The title compound was prepared from the product of preparation 61 andphosphorous oxychloride, using the method of preparation 13. The crudeproduct was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 99:1 to 98:2, to afford the desiredcompound as a beige solid in 15% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 2.43 (s, 3H), 3.53 (s, 3H), 4.80 (s, 2H), 7.06(m, 2H), 7.46 (m, 1H), 7.74 (d, 1H) 8.43 (d, 1H). MS APCl+ m/z 301 [MH]⁺

Preparation 63 5-Bromo-pyrimidine-2-carbonitrile

A solution of 5-bromo-2-chloropyrimidine (10 g, 51.8 mmol) indimethylsulfoxide (26 mL) was added to a mixture of sodium cyanide (2.59g, 51.8 mmol) and triethylenediamine (1.2 g, 10.4 mmol) indimethylsulfoxide (14 mL) and water (28 mL). The resulting mixture wasstirred for 18 hours at room temperature. The mixture was then dilutedwith water (130 mL) and extracted with diethyl ether (3×150 mL). Thecombined organic solutions were dried over sodium sulfate andconcentrated in vacuo to give a pale yellow solid. Re-crystallisation ofthe solid from hot dichloromethane afforded the title product in 99%yield, 9.4 g.

¹HNMR (CDCl₃, 400 MHz) δ: 8.84 (s, 2H).

Preparation 64 5-Bromo-pyrimidine-2-carboxylic acid

A mixture of sodium hydroxide (4.88 g, 120 mmol) and the product ofpreparation 63 (7.5 g, 40.8 mmol) in water (122 mL) was heated at 60° C.for 1 hour. The mixture was then acidified with 1M hydrochloric acid,extracted with ethyl acetate and dichloromethane and concentrated invacuo to afford some title compound as a white solid, 300 mg. Theaqueous solution was also evaporated under reduced pressure and theresidue was extracted into dichloromethane:methanol, 90:10. Theprecipitate was filtered off and the filtrate was concentrated in vacuoto afford further title compound as a white solid, 5.5 g.

¹HNMR (DMSO-D₆, 400 MHz) δ: 9.10 (s, 2H), 13.8 (brs, 1H). MS APCl+ m/z203 [MH]⁺

Preparation 65 5-Bromo-pyrimidine-2-carboxylic acid methyl ester

Fuming hydrochloric acid was passed through an ice-cooled solution ofthe product of preparation 64 (5.5 g, 27 mmol) in methanol (50 mL) untilsaturated. The reaction mixture was warmed to room temperature and wasstirred for 18 hours. The solvent was then evaporated under reducedpressure and the residue was dissolved in dichloromethane, washed withwater and sodium hydrogen carbonate solution, dried over magnesiumsulfate and concentrated in vacuo to afford the title compound as yellowsolid in 57% yield, 3.5 g.

¹HNMR (CDCl₃, 400 MHz) δ: 4.05 (s, 3H), 9.00 (s, 2H). MS APCl+ m/z 218[MH]⁺

Preparation 66 5-Bromo-pyrimidine-2-carboxylic acid hydrazide

The title compound was prepared from the product of preparation 65 andhydrazine monohydrate, using the method of preparation 6, as a yellowsolid in quantitative yield.

¹HNMR (CDCl₃, 400 MHz) δ: 4.20 (s, 2H), 8.90 (m, 3H). MS APCl+ m/z 217[MH]⁺

Preparation 67 5-Bromo-pyrimidine-2-carboxylic acidN′-(2-methoxy-acetyl)-hydrazide

The title compound was prepared from the product of preparation 66 andmethoxyacetyl chloride, using the method of preparation 8, as a whitesolid in 45% yield.

¹HNMR (DMSO-D₆, 400 MHz) δ: 3.32 (s, 3H), 3.98 (s, 2H), 9.20 (s, 2H),10.02 (s, 1H), 10.66 (s, 1H). MS APCl+ m/z 290 [MH]⁺

Preparation 685-Bromo-2-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyrimidine

The title compound was prepared from the product of preparation 67,using the method of preparation 13. The crude product was purified bycolumn chromatography on silica gel, eluting withdichloromethane:methanol, 99.5:0.5 to 99:1, to afford the desiredcompound as a white solid in 45% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 3.52 (s, 3H), 4.78 (s, 2H), 9.02 (s, 2H). MSAPCl+ m/z 271 [MH]⁺

Preparation 695-(4-Fluoro-2-methyl-phenyl)-2-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyrimidine

A solution of sodium carbonate (295 mg, 2.78 mmol) in water (3 mL) wasadded to a solution of the product of preparation 68 (376 mg, 1.39mmol), 4-fluoro-2-methylphenyl boronic acid (320 mg, 2.08 mmol) andpalladium triphenylphosphine (48 mg, cat) in 1,2-dimethoxyethane (3 mL)and the mixture was heated under reflux for 2 hours. The reactionmixture was then evaporated under reduced pressure and the residue waspartitioned between water and ethyl acetate. The resulting precipitatewas filtered off, washing through with water, ethyl acetate and diethylether, and dried to afford the title compound as a beige solid in 59%yield, 332 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.33 (s, 3H), 3.53 (s, 3H), 4.81 (s, 2H), 7.09(m, 2H) 7.25 (m, 1H), 8.90 (s, 2H). MS APCl+ m/z 301 [MH]⁺

Preparation 70 5-Bromo-2-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridine

The title compound was prepared from the product of preparation 6 andN,N-dimethylacetamide dimethyl acetal, using the method of preparation4, as a white solid in 47% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 2.65 (s, 3H), 8.01 (m, 1H), 8.12 (m, 1H), 8.80(m, 1H). MS APCl+ m/z 240/242 [MH]⁺

Preparation 713-[3-(5-Bromo-pyridin-2-yl)-5-methyl-[1,2,4]triazol-4-yl]-2,6-dimethoxy-pyridine

3-Amino-2,6-dimethoxypyridine monohydrochloride (2 g, 13 mmol) waspartitioned between sodium carbonate solution and ethyl acetate. Theorganic layer was separated, washed with brine, dried over sodiumsulfate and concentrated in vacuo to afford the free base. The base wasthen dissolved in xylene (30 mL) and the product of preparation 70 (1.8g, 7.5 mmol) and para-toluenesulfonic acid (50 mg, cat) were added. Theresulting mixture was heated under reflux for 18 hours. The reactionmixture was concentrated in vacuo and the residue purified by columnchromatography on silica gel eluting with dichloromethane:methanol 100:0to 98:2, to afford the title product as a purple solid in 23% yield, 628mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.49 (s, 3H), 3.80 (s, 3H), 3.98 (s, 3H), 6.41(d, 1H), 7.45 (d, 1H), 7.92 (dd, 1H), 8.11 (d, 1H), 8.37 (d, 1H). MSAPCl+ m/z 377 [MH]⁺

Preparation 725-(4-Fluoro-2-methyl-phenyl)-2-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridine

A mixture of the product of preparation 40 (545 mg, 2.79 mmol),4-fluoro-2-methylphenyl boronic acid (643 mg, 4.18 mmol), caesiumcarbonate (2.7 g, 8.29 mmol) and the product of preparation 3 (10 mg,cat.) in 1,4-dioxan (25 mL) was heated under reflux for 4 hours. Thereaction mixture was then cooled to room temperature, filtered throughCelite® and concentrated in vacuo to afford the title compound as a paleyellow solid in quantitative yield.

¹HNMR (CDCl₃, 400 MHz) δ: 2.40 (s, 3H), 2.66 (s, 3H), 7.00 (m, 2H), 7.43(dd, 1H), 7.53 (d, 1H), 8.37 (d, 1H) 9.29 (d, 1H). MS APCl+ m/z 270[MH]⁺

Preparations 73 to 81

The following compounds of the general formula shown below were preparedin quantitative yield, by the method of preparation 72, using theappropriate oxadiazole (preparations 14-16) and boronic acid.

The progress of the reactions was monitored by tlc analysis and themixtures were heated under reflux until all of the starting materialshad been consumed.

No. R¹ R² Y Data 73

H N ¹HNMR(CDCl₃, 400 MHz) δ: 2.29(s, 3H), 2.37(s, 3H), 2.70(s, 3H),7.21- 7.34(m, 3H), 8.81(d, 1H), 9.51(d, 1H). MS ES+ m/z 289 [MNa]⁺ 74

H N ¹HNMR(CDCl₃, 400 MHz) δ: 2.46(s, 3H), 2.70(s, 3H), 7.06(m, 2H),7.50(m, 1H), 8.82(d, 1H), 9.49(d, 1H). MS ES+ m/z 293 [MNa]⁺ 75

OCH₃ CH ¹HNMR(CDCl₃, 400 MHz) δ: 2.41(s, 3H), 3.52(s, 3H), 4.75(s, 2H),6.94- 7.04(m, 2H), 7.44(dd, 1H), 7.55(dd, 1H), 8.42(d, 1H), 9.35(dd,1H). MS APCl+ m/z 300 [MH]⁺ 76

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 2.46(s, 3H), 3.53(s, 3H), 4.79(s, 2H),7.06(m, 2H), 7.51(m, 1H), 8.84(d, 1H), 9.51(d, 1H). MS APCl+ m/z 301[MH]⁺ 77

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 2.40(d, 3H), 3.52(s, 3H), 4.51(s, 2H),7.23-7.30(m, 3H), 9.06(s, 1H), 9.40(s, 1H) MS ES+ m/z 433 [MCs]⁺ 78

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 3.78(s, 3H), 4.09(s, 3H), 4.80(s, 2H),7.01-7.18(m, 2H), 7.54-7.72(m, 1H), 9.26(s, 1H), 9.57(s, 1H) MS ES+ m/z449 [MCs]⁺ 79

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 2.37(s, 3H), 3.52(s, 3H), 3.89(s, 3H),4.78(s, 2H), 6.95(d, 1H), 7.25(m, 1H), 7.77(m, 1H), 9.35(d, 1H), 9.49(d,1H). MS ES+ m/z 445 [MCs]⁺ 80

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 3.52(s, 3H), 3.91(s, 3H), 4.78(s, 2H),6.99(m, 1H), 7.17(m, 1H), 7.77(m, 1H), 9.41(d, 1H), 9.50(d, 1H). MS ES+m/z 461 [MCs]⁺ 81

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 2.39(s, 3H), 2.40(s, 3H), 3.53(s, 3H),4.79(s, 2H), 7.03-7.41(m, 2H), 8.86(s, 1H), 9.52(d, 1H). MS ES+ m/z 429[MCs]⁺

Preparation 82 Methyl-(5-nitro-pyridin-2-yl)-amine

Methylamine gas was bubbled through a stirred solution of2-chloro-5-nitropyridine (4 g, 25.2 mmol) in dichloromethane (60 mL), atroom temperature, until saturation had occurred. The resulting yellowprecipitate was then filtered off, washed with dichloromethane and driedunder vacuum to afford the title compound as a yellow solid in 80%yield, 3.07 g.

¹HNMR (CDCl₃, 400 MHz) δ: 3.05 (d, 3H), 5.41 (bs, 1H), 6.37 (d, 1H),8.21 (d, 1H), 9.03 (d, 1H). MS APCl+ m/z 154 [MH]⁺

Preparation 83 N*2*-Methyl-pyridine-2,5-diamine

The product of preparation 82 (3.0 g, 19.5 mmol) and 10% Pd/C (300 mg,cat.) were stirred in ethanol (150 mL) under 60 psi of hydrogen gas for18 hours. The reaction mixture was then filtered through Celite® and thefiltrate was concentrated in vacuo to afford the title product in 17%yield, 400 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.85 (s, 3H), 3.19 (s, 2H), 4.11 (s, 1H), 6.31(d, 1H), 6.97 (dd, 1H), 7.69 (d, 1H). MS APCl+ m/z 269 [MNa]⁺

Preparation 84 4,6-Dichloro-nicotinic acid methyl ester

3-Pyridinecarboxylic acid [(27 g, 160 mmol), J. Het. Chem., 20, 1363;1983] was added portionwise to phosphorus oxychloride (180 mL) and themixture was heated under reflux for 7 hours and stirred at roomtemperature for 18 hours. The mixture was then concentrated in vacuo toa low volume and the residue was quenched with water. The aqueousmixture was neutralised with sodium hydrogen carbonate solution andextracted with chloroform (3×150 mL). The combined organic solutionswere washed with brine, dried over sodium sulfate and concentrated invacuo to afford the title compound as a red oil in 83% yield, 27.2 g.

¹HNMR (CDCl₃, 400 MHz) δ: 3.96 (s, 3H), 7.47 (s, 1H), 8.85 (s, 1H). MSAPCl+ m/z 206 [MH]⁺

Preparations 85 and 86

Sodium methoxide (0.5M in methanol, 48.6 mL, 24.3 mmol) was addeddropwise to an ice-cold solution of the product of preparation 84 (5.0g, 24.3 mmol) in methanol (20 mL). The mixture was allowed to warm toroom temperature and was stirred for 2 hours. The solvent was thenevaporated under reduced pressure and the residue was partitionedbetween water (50 mL) and chloroform (50 mL). The layers were separatedand the aqueous layer was extracted with chloroform (2×75 mL). Thecombined organic solutions were then dried over sodium sulphate andconcentrated in vacuo to give an orange oil. The oil was purified bycolumn chromatography on silica gel, eluting with dichloromethane (100%)to afford the product of preparation 85 as a white solid in 7.6% yield,370 mg. Further elution with dichloromethane then isolated the productof preparation 86 as a white solid in 27% yield, 1.32 g.

Preparation 85 4-Chloro-6-methoxy-nicotinic acid methyl ester

¹HNMR (CDCl₃, 400 MHz) δ: 3.90 (s, 3H), 3.96 (s, 3H), 6.81 (s, 1H), 8.71(s, 1H). MS APCl+ m/z 202 [MH]⁺

Preparation 86 6-Chloro-4-methoxy-nicotinic acid methyl ester

¹HNMR (CDCl₃, 400 MHz) δ: 3.87 (s, 3H), 3.94 (s, 3H), 6.90 (s, 1H), 8.68(s, 1H). MS APCl+ m/z 202 [MH]⁺

Preparation 87 6-Chloro-4-methoxy-nicotinic acid hydrazide

Hydrazine monohydrate (690 μL, 14.2 mmol) was added to a suspension ofthe product of preparation 86 (2.7 g, 13.4 mmol) in methanol (35 mL),cooled to −5° C., and the mixture was stirred for 3 hours. The mixturewas then warmed to room temperature and was stirred for 18 hours. Theresulting precipitate was filtered off and dried to afford some titlecompound as a white solid, 990 mg. Tlc analysis of the filtrate showedthat not all of the starting material had been consumed and so furtherhydrazine monohydrate (267 μL, 5.51 mmol) was added and the reactionmixture was stirred for 24 hours. The resulting precipitate wascollected by filtration and dried to afford a further crop of titlecompound as a yellow solid, 832 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 3.92 (s, 3H), 4.55 (bd, 2H), 7.29 (s, 1H),8.37 (s, 1H), 9.38 (m, 1H). MS APCl+ m/z 247 [MH]⁺

Preparation 88 6-Chloro-4-methoxy-nicotinic acidN′-(2-methoxy-acetyl)-hydrazide

Methoxyacetyl chloride (733 L, 8.02 mmol) was added to an ice-coldsuspension of the product of preparation 87 (1.16 g, 5.73 mmol) indichloromethane (20 mL) and triethylamine (1.2 mL, 8.61 mmol) and themixture was stirred for 18 hours at room temperature. The reactionmixture was then washed with water and brine, dried over sodium sulphateand concentrated in vacuo to give a pale yellow gum. The gum waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol, 100:0:0 to 95:5, to afford the title compoundas a clear glass in 31% yield, 480 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 3.48 (s, 3H), 4.08 (s, 3H), 4.10 (s, 2H), 6.96(s, 1H), 9.03 (s, 1H), 9.25 (d, 1H), 9.99 (d, 1H). MS APCl+ m/z 274/276[MH]⁺

Preparation 892-Chloro-4-methoxy-5-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-pyridine

The title compound was prepared form the product of preparation 88 andphosphorus oxychloride, using the method of preparation 13, as a yellowoil in quantitative yield.

¹HNMR (CDCl₃, 400 MHz) δ: 3.49 (s, 3H), 4.04 (s, 3H), 4.73 (s, 2H), 7.01(s, 1H), 8.83 (s, 1H). MS APCl+ m/z 256 [MH]⁺

Preparation 902-Chloro-4-methoxy-5-[5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridine

The title compound was prepared from the product of preparation 89 and5-amino-2-methoxypyridine, using the method of preparation 18, as a paleyellow foam in 29% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 3.37 (s, 3H), 3.61 (s, 3H), 3.93 (s, 3H), 4.49(s, 2H), 6.76 (m, 2H), 7.43 (dd, 1H), 7.98 (d, 1H), 8.42 (s, 1H). MSAPCl+ m/z 362 [MH]⁺

Preparation 91 5-(4-Fluoro-2-methyl-phenyl)-pyrazine-2-carboxylic acidmethyl ester

4-Fluoro-2-methylphenyl boronic acid (17.36 g, 112.7 mmol), caesiumcarbonate (70.8 g, 216.8 mmol) and the product of preparation 3 (1.5 mg,8.67 mmol.) were added to a solution of5-chloropyrazine-2-methylcarboxylate (15 g, 86.7 mmol) in 1,4-dioxan (2L) and the mixture was heated under reflux for 2 hours. The reactionmixture was then filtered and concentrated in vacuo to afford the titlecompound in 99% yield, 21.33 g.

¹HNMR (CDCl₃, 400 MHz) δ: 2.40 (s, 3H), 4.05 (s, 3H), 7.05 (m, 2H), 7.45(m, 1H), 8.80 (1, 1H), 9.35 (s, 1H). MS APCl+ m/z 247 [MH]⁺

Preparation 92 5-(4-Fluoro-2-methyl-phenyl)-pyrazine-2-carboxylic acidhydrazide

A mixture of the product of preparation 91 (42.5 g, 172.8 mmol) andhydrazine monohydrate (9.46 mL, 207.3 mmol) in methanol (600 mL) washeated under reflux for 30 hours. The reaction mixture was then cooledto room temperature and the precipitate was filtered off and dried invacuo to afford the title compound in 75% yield, 7.10 g.

¹HNMR (DMSO, 400 MHz) δ: 2.35 (s, 3H), 4.60 (s, 2H), 7.20 (m, 2H), 7.60(m, 1H), 8.80 (s, 1H), 9.15 (s, 1H), 10.2 (s, 1H).

Examples 1-4

The bromo compound of preparation 5 (100 mg, 0.29 mmol), the palladiumcomplex of preparation 3 (10 mg, cat.), caesium carbonate (440 mg, 1.35mmol) and the appropriate boronic acid (0.73 mmol) were suspended in1,4-dioxan (5 mL) and the reaction mixture heated to 120° C. for 90minutes. Additional 1,4-dioxan (4 mL) was added and the reaction mixtureheated to 100° C. for a further 4 hours. The reaction mixture wasfiltered under vacuum, washing through with dichloromethane. Thefiltrate was concentrated in vacuo and the residue purified by columnchromatography on silica gel eluting with dichloromethane:methanol:0.88ammonia 95:5:0.5 to yield the desired product.

No. R¹ Data Yield 1

MS ES+ m/z 390 [MH]⁺ 9% 2

¹HNMR(CDCl₃, 400 MHz) δ: 2.01(s, 3H), 2.22(s, 3H), 2.26(s, 3H), 3.75(s,3H), 6.87(d, 1H), 7.02(m, 4H), 7.20(m, 2H), 7.24(m, 2H), 7.39(m, 2H) MSAPCl+ m/z 370 [MH]⁺ 10% 3

MS APCl+ m/z 370 [MH]⁺ 36% 4

¹HNMR(CDCl₃, 400 MHz) δ: 2.31(s, 3H), 3.79(s, 3H), 3.83(s, 3H), 7.02(m,3H), 7.27(m, 2H), 7.34(d, 2H), 7.41(d, 2H), 7.57(d, 2H). MS APCl+ m/z390 [MH]⁺ 52%

Example 52-(4-Fluoro-2-methylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine

The title product was prepared by the method of preparation 18 using theproduct of preparation 19 and 5-amino-2-methoxypyridine. 140 mg, 15%yield of the desired product was produced.

¹HNMR (CDCl₃, 400 MHz) δ: 2.36 (s, 3H), 3.38 (s, 3H), 4.01 (s, 3H), 4.51(s, 2H), 6.88 (d, 1H), 6.93-7.00 (m, 2H), 7.36 (dd, 1H), 7.40 (d, 1H),7.56 (dd, 1H), 8.00 (dd, 1H), 8.15 (d, 1H), 8.64 (d, 1H). Microanalysis:C₂₂H₂₀FN₅O₂ requires; C, 65.18; H, 4.97; N, 17.27. found C, 65.01; H,4.96; N, 17.27. MS APCl+ m/z 406 [MH]⁺

Example 62-(2,3-Dimethylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine

The title product was prepared by the method of preparation 18 using theproduct of preparation 20 and 5-amino-2-methoxypyridine. 325 mg, 36% ofthe desired product was produced.

¹HNMR (CDCl₃, 400 MHz) δ: 2.21 (s, 3H), 2.34 (s, 3H), 3.38 (s, 3H), 4.00(s, 3H), 4.52 (s, 2H), 6.88 (d, 1H), 7.13-7.22 (m, 3H), 7.40 (d, 1H),7.55 (d, 1H), 7.99 (dd, 1H), 8.16 (d, 1H), 8.64 (d, 1H). Microanalysis:C₂₃H₂₃N₅O₂. 0.1H₂O requires; C, 68.50; H, 5.80; N, 17.37. found C,68.24; H, 5.90; N, 17.05. MS APCl+ m/z 402 [MH]⁺

Example 75-(4-Fluoro-2-methylphenyl)-2-(((5-methoxymethyl-4-(6-methoxypyridin-3-yl))-4H-[1,2,4]triazol-3-yl)-pyridine

The bromo compound of preparation 18 (250 mg, 0.66 mmol),2-methyl-4-fluoro-phenylboronic acid (235 mg, 1.53 mmol), the palladiumcomplex of preparation 3 (10 mg, cat.) and caesium carbonate (1.00 g,3.07 mmol) were added to 1,4-dioxan (15 mL) and the reaction mixtureheated to 110° C. for 4 hours. The reaction mixture was filtered throughArbocel®, washed through with dichloromethane and the filtrateconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with dichloromethane:methanol 100:0 to 95:5 toyield the title product, 128 mg, 48% yield as a pale pink solid.

¹HNMR (DMSO-D₆, 400 MHz) δ: 2.21 (s, 3H), 3.18 (s, 3H), 3.89 (s, 3H),4.44 (s, 2H), 6.94 (m, 1H), 7.09 (m, 1H), 7.19 (m, 1H), 7.28 (m, 1H),7.81 (m, 1H), 7.94 (m, 1H), 8.15 (m, 1H), 8.23 (m, 1H), 8.32 (m, 1H). MSAPCl+ m/z 406 [MH]⁺

Example 85-(2,3-Dimethylphenyl)-2-[5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridine

The title product was prepared by the method of example 7 using2,3-dimethylphenylboronic acid. 132 mg, 49% yield of the desired productwas prepared as a pale pink solid.

¹HNMR (DMSO-D₆, 400 MHz) δ: 2.07 (s, 3H), 2.38 (s, 3H), 3.17 (s, 3H),3.89 (s, 3H), 4.44 (s, 2H), 6.94 (m, 1H), 7.04 (m, 1H), 7.15 (m, 1H),7.22 (m, 1H), 7.82 (m, 1H), 7.90 (m, 1H), 8.15 (m, 1H), 8.24 (m, 1H),8.28 (m, 1H). MS APCl+ m/z 402 [MH]⁺

Example 91-[5-[5-(2,3-Dimethylphenyl)-pyridin-2-yl]-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-ylmethyl]-pyrrolidine-(2S)-2-carboxylicacid amide

The bromo compound of preparation 27 (125 mg, 0.27 mmol),2,3-dimethylphenyl boronic acid (61 mg, 0.41 mmol) and the palladiumcomplex of preparation 3 (10 mg) were dissolved in 1,2-dimethoxyethane(4 mL) and the solution was treated with sodium carbonate (58 mg, 0.55mmol). The reaction mixture was heated to reflux for 1 hour and thenconcentrated in vacuo. The residue was taken up in ethyl acetate (25 mL)and washed with water (25 mL), 2M sodium hydroxide solution (25 mL) andbrine (25 mL). The solution was dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with dichloromethane:methanol:0.88 ammonia 100:0:0to 97:3:0.3 to yield the title product, 95 mg, 72% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 1.80 (m, 2H), 2.00 (m, 1H), 2.10 (s, 3H), 2.20(m, 1H), 2.40 (s, 3H), 2.60 (m, 1H), 3.20 (m, 2H), 3.80 (m, 2H), 4.00(s, 3H), 5.00 (s, 1H), 6.80 (s, 1H), 6.90 (d, 1H), 7.00 (d, 1H), 7.10(d, 1H), 7.20 (d, 1H), 7.60 (d, 1H), 7.70 (d, 1H), 8.80 (s, 1H), 8.20(m, 2H). MS ES+ m/z 484 [MH]⁺

Example 105-(2,3-Dimethylphenyl)-2-(5-pyrrolidin-1-ylmethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl)-pyridine

80 mg, 38% yield of the title product was prepared by the method ofexample 9 using the bromo compound of preparation 28.

¹HNMR (CDCl₃, 400 MHz) δ: 1.80 (s, 4H), 2.10 (s, 3H), 2.40 (s, 3H), 2.50(s, 4H), 3.70 (s, 2H), 4.00 (s, 3H), 6.80 (d, 1H), 7.00 (d, 1H), 7.20(m, 2H), 7.70 (t, 2H), 8.10 (d, 1H), 8.20 (d, 1H), 8.30 (s, 1H). MS ES+m/z 441 [MH]⁺

Example 112-(4-Fluoro-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine

The product of preparation 22 (450 mg, 1.50 mmol), para-toluenesulfonicacid monohydrate (30 mg) and 5-amino-2-methoxypyridine (205 mg, 1.65mmol) were added to xylene (8 mL) and the reaction mixture heated to145° C. for 18 hours. The reaction mixture was concentrated in vacuo andthe residue purified by column chromatography on silica gel eluting withdichloromethane:methanol:0.88 ammonia 100:0:0 to 99.5:0.5:0.05 to99:1:0.1 to yield the title product, 300 mg, 49% yield as a green solid.

¹HNMR (CDCl₃, 400 MHz) δ: 2.38 (s, 3H), 3.34 (s, 3H), 3.99 (s, 3H), 4.50(s, 2H), 6.85 (d, 1H), 6.95-7.03 (m, 2H), 7.36-7.42 (m, 1H), 7.60 (dd,1H), 8.12 (d, 1H), 8.40 (s, 1H), 9.48 (s, 1H). MS APCl+ m/z 407 [MH]⁺

Example 122-(2,3-Dimethylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine

42 mg, 7% yield of the title product was prepared by the method ofexample 11, using the product of preparation 21.

¹HNMR (CDCl₃, 400 MHz) δ: 2.23 (s, 3H), 2.34 (s, 3H), 3.36 (s, 3H), 4.00(s, 3H), 4.50 (m, 2H), 6.86 (d, 1H), 7.19 (d, 1H), 7.20 (s, 1H), 7.24(m, 1H), 7.62 (dd, 1H), 8.14 (d, 1H), 8.41 (d, 1H), 9.49 (d, 1H). MSAPCl+ m/z 403 [MH]⁺

Example 132-(2,3-Dimethylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine

The title product was prepared by the method of example 11 using theproduct of preparation 23. 14 mg, 3% of the desired product was producedas a white solid.

¹HNMR (CDCl₃, 400 MHz) δ: 2.22 (s, 3H), 2.34 (s, 3H), 2.39 (s, 3H), 4.01(s, 3H), 6.88 (d, 1H), 7.18-7.25 (m, 3H), 7.52 (dd, 1H), 8.09 (d, 1H),8.37 (s, 1H), 9.49 (s, 1H). MS APCl+ m/z 373 [MH]⁺

Example 142-(4-Fluoro-2-methylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine

The chloro compound of preparation 30 (800 mg, 2.60 mmol),4-fluoro-2-methylphenyl boronic acid (470 mg, 3.12 mmol), the palladiumcomplex of preparation 3 (5 mg) and caesium carbonate (2.50 g, 7.90mmol) were added to 1,4-dioxan (80 mL) and the reaction mixture heatedto reflux for 2 hours. The mixture was filtered through a filter tubeand then filtered through a pad of silica eluting withdichloromethane:methanol 96:4. The filtrate was concentrated in vacuoand purified by column chromatography on silica gel, eluting withdichloromethane:methanol 100:0 to 95:5 to afford the title product as awhite solid in 66% yield, 646 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.39 (s, 3H), 2.41 (s, 3H), 4.01 (s, 3H), 6.89(d, 1H), 6.95-7.03 (m, 2H), 7.38 (dd, 1H), 7.54 (dd, 1H), 8.09 (d, 1H),8.38 (d, 1H), 9.49 (d, 1H). MS APCl+ m/z 377 [MH]⁺

Alternative Method

Dimethylacetamide dimethylacetal (28 mL, 192.1 mmol) was added to asuspension of the product of preparation 92 (31.5 g, 127.9 mmol) inglacial acetic acid (315 mL) and the mixture was heated at 60° C. for 5hours. 5-Amino-2-methoxy pyridine (23.9 g, 192 mmol) was added and themixture was heated at 100° C. for a further 6 hours. The mixture wasthen cooled to room temperature and evaporated under reduced pressure.The residue was taken up in dichloromethane (750 mL) and washed withsaturated sodium hydrogen carbonate solution (1 L). The organic solutionwas dried over magnesium sulfate and concentrated in vacuo.Re-crystallisation of the residue from hot acetone then afforded thetitle compound as a white solid in 31% yield, 14.81 g.

Example 152-(4-Cyano-2-methylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine

The title product was prepared by the method of example 14 using thechloro compound of preparation 30 (200 mg, 0.66 mmol) and the product ofpreparation 29 (240 mg, 0.99 mmol). 68 mg, 27% yield of the titleproduct was prepared as a white solid.

¹HNMR (CDCl₃, 400 MHz) δ: 2.40 (s, 3H), 2.43 (s, 3H), 4.01 (s, 3H), 6.90(d, 1H), 7.50-7.55 (m, 2H), 7.57 (s, 1H), 7.60 (s, 1H), 8.08 (d, 1H),8.41 (d, 1H), 9.55 (d, 1H). Microanalysis: C₂₁H₁₇N₇O 0.1; H₂O requires;C, 65.79; H, 4.47; N, 25.57. found C, 65.23; H, 4.48; N, 25.09. MS APCl+m/z 384 [MH]⁺

Example 162-(5-Fluoro-2-methoxyphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazine

The title product was prepared by the method of example 14 using thechloro compound of preparation 30 (200 mg, 0.66 mmol) and5-fluoro-2-methoxyphenyl boronic acid (168 mg, 0.99 mmol). 150 mg, 58%yield of the title product was prepared as a cream solid.

¹HNMR (CDCl₃, 400 MHz) δ: 2.37 (s, 3H), 3.85 (s, 3H), 4.00 (s, 3H), 6.88(d, 1H), 6.92 (dd, 1H), 7.09 (m, 1H), 7.50 (dd, 1H), 7.68 (dd, 1H), 8.07(d, 1H), 8.93 (d, 1H), 9.46 (d, 1H).

Example 172-(4-Cyano-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine

The title product was prepared by the method of example 14 using thechloro compound of preparation 31 (1.0 g, 3.0 mmol) and preparation 29(1.02 g, 4.2 mmol). 814 mg, 66% yield of the desired product wasprepared as a pale yellow solid.

¹HNMR (CDCl₃, 400 MHz) δ: 2.35 (s, 3H), 3.15 (s, 3H), 3.80 (s, 3H), 4.45(s, 2H), 6.95 (d, 1H), 7.65-7.90 (m, 4H). MS APCl+ m/z 414 [MH]⁺

Example 185-(4-Cyano-2-methylphenyl)-2-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridine

The title product was prepared by the method of example 7 using theproduct of preparation 29 (100 mg, 0.41 mmol) and the bromo compound ofpreparation 18 (155 mg, 0.41 mmol). 67 mg 39% yield of the desiredproduct was prepared as a white solid.

¹HNMR (CDCl₃, 400 MHz) δ: 2.28 (s, 3H), 3.35 (s, 3H), 3.99 (s, 3H), 4.50(s, 2H), 6.85 (d, 1H), 7.28 (d, 1H), 7.52-7.58 (m, 2H), 7.62 (dd, 1H),7.74 (dd, 1H), 8.11 (d, 1H), 8.28 (dd, 1H), 8.33 (1H, d). Microanalysis:C₂₃H₂₀N₆O_(2□)0.5H₂O requires; C, 66.55; H, 5.02; N, 19.94. found C,66.02; H, 4.90; N, 19.83. MS APCl+ m/z 413 [MH]⁺

Example 192-(5-Fluoro-2-methoxyphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridine

The title compound was prepared using the method of example 11, usingthe oxadiazole compound of preparation 32 and 5-amino-2-methoxypyridine, as a pale green solid (325 mg, 30%).

¹HNMR (CDCl₃, 400 MHz) δ: 3.36 (s, 3H), 3.84 (s, 3H), 3.98 (s, 3H), 4.49(s, 2H), 6.87 (d, 1H), 6.92 (dd, 1H), 7.06 (m, 1H), 7.54 (dd, 1H), 7.58(dd, 1H), 7.96-8.00 (m, 2H), 8.14 (d, 1H), 8.60 (d, 1H). MS APCl+ m/z422 [MH]⁺

Examples 20-22

The following compounds, of the general formula shown below, wereprepared by the method of examples 1-4 using the products ofpreparations 46 or 47 and the appropriate boronic acid.

The crude compounds were purified firstly by column chromatography onsilica gel, eluting with ethyl acetate:methanol:0.88 ammonia, 100:0:0 to99:1:0.1 to 95:5:0.5, followed by purification by HPLC using aPhenomenex Luna C18 system, eluting withwater/acetonitrile/trifluoroacetic acid (5:95:0.1):acetonitrile, 95:5 to5:95.

No. R¹ Y Data Yield 20

CH ¹HNMR(CDCl₃, 400 MHz) δ: 2.37 (s, 3H), 3.97(s, 3H), 5.77(s, 2H),6.80(d, 1H), 7.31(dd, 1H), 7.45(m, 2H), 7.56(m, 4H), 7.99(d, 1H),8.04(dd, 1H), 8.66(dd, 1H). MS APCl+ m/z 450 [MH]⁺ 21% 21

N ¹HNMR(CDCl₃, 400 MHz) δ: 2.40 (s, 3H), 3.97(s, 3H), 5.77(s, 2H),6.75(d, 1H), 7.35(dd, 1H), 7.50(d, 1H), 7.54-7.67(m, 4H), 7.95(d, 1H),8.41(s, 1H), 9.58(s, 1H). MS APCl+ m/z 450 [MH]⁺ 15% 22

CH ¹HNMR(CDCl₃, 400 MHz) δ: 2.34 (s, 3H), 3.97(s, 3H), 5.77(s, 2H),6.78(d, 1H), 6.95(m, 2H), 7.30(dd, 1H), 7.35(dd, 1H), 7.42(dd, 1H),7.57(s, 2H), 8.00(m, 2H), 8.60(d, 1H) MS APCl+ m/z 443 [MH]⁺ 43%

Example 234-{5-[5-(Methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}-3-methylbenzonitrile

The chloro compound of preparation 49 (170 mg, 0.87 mmol), the palladiumcomplex of preparation 3 (5 mg, cat.), caesium carbonate (847 mg, 2.61mmol) and the product of preparation 29 (317 mg, 1.31 mmol) weresuspended in 1,4-dioxan (5 mL) and the reaction mixture heated to 110°C. for 2 hours. The reaction mixture was diluted with ethyl acetate andwater, and filtered through Celite®. The layers of the filtrate wereseparated and the aqueous solution was re-extracted with ethyl acetate(×2). The combined organic solutions were then washed with brine, driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel eluting withdichloromethane:methanol:0.88 ammonia 100:0:0 to 97.5:2.5:0.25 to affordthe title compound as a white foam in 45% yield, 160 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.38 (s, 3H), 3.38 (s, 3H), 4.00 (s, 3H), 4.51(s, 2H), 6.90 (d, 1H), 7.45 (d, 1H), 7.48 (d, 1H), 7.55-7.60 (m, 3H),8.03 (dd, 1H), 8.15 (d, 1H), 8.70 (dd, 1H). MS APCl+ m/z 413 [MH]⁺

Examples 24 to 28

The following compounds, of the general formula shown below, wereprepared by the method of example 23, using the appropriate triazolecompounds (preparations 31 and 50-51) and boronic acids.

No. R¹ Y R² Yield 24

CH H 37% Data ¹HNMR(CDCl₃, 400 MHz) δ: 2.38(s, 3H), 2.41(s, 3H), 4.00(s,3H), 6.92(d, 1H), 7.45(m, 3H), 7.55(s, 1H), 7.58(s, 1H), 8.02(dd, 1H),8.12(d, 1H), 8.66(d, 1H). Microanalysis: C₂₂H₁₈N₆O requires; C 69.10, H4.74, N 21.98 found C 68.74, H 4.75, N 21.83. MS APCl+ m/z 383 [MH]⁺ 25

CH H 83% Data ¹HNMR(CDCl₃, 400 MHz) δ: 2.39(s, 3H), 3.83(s, 3H), 3.99(s,3H), 6.88-6.94(m, 2H), 7.05(m, 1H), 7.45(dd, 1H), 7.58(s, 1H), 7.97(m,2H), 8.11(d, 1H), 8.57(d, 1H). MS APCl+ m/z 392 [MH]⁺ 26

N OCH₃ 35% Data ¹HNMR(CDCl₃, 400 MHz) δ: 3.35(s, 3H), 3.86(s, 3H),4.00(s, 3H), 4.49(s, 2H), 6.71 (dd, 1H), 6.80(m, 1H), 6.85(d, 1H),7.59(dd, lH), 7.91(dd, 1H), 8.12(d, 1H), 8.88(d, 1H), 9.44(d, 1H). MSAPCl+ m/z 423 [MH]⁺ 27

CH

31% Data ¹HNMR(CDCl₃, 400 MHz) δ: 2.38(s, 3H), 3.34(s, 3H), 3.50(m, 2H),3.66(m, 2H), 3.99(s, 3H), 4.62(s, 2H), 6.88(d, 1H), 7.44(d, 1H), 7.48(d,1H), 7.56(d, 2H), 7.66(dd, 1H), 8.02(dd, 1H), 8.15(d, 1H), 8.70(d, 1H).Microanalysis: C₂₅H₂₄N₆O₃ 0.5H₂O requires; C 64.50, H 5.41, N 18.05;found C 64.71, H 5.33, N 17.94. MS APCl+ m/z 457 [MH]⁺ 28

CH

90% Data ¹HNMR(CDCl₃, 400 MHz) δ: 2.35(s, 3H), 3.34(s, 3H), 3.50(m, 2H),3.66(m, 2H), 3.98(s, 3H), 4.62(s, 2H), 6.87(d, 1H), 6.93-7.00(m, 2H),7.36(dd, 1H), 7.41(d, 1H), 7.65(dd, 1H), 7.97(dd, 1H), 8.15(d, 1H),8.64(d, 1H). MS APCl+ m/z 450 [MH]⁺

Example 29[5-[6-(4-Fluoro-2-methyl-phenyl)-pyridin-3-yl]-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-ylmethyl]-dimethyl-amine

The title compound was prepared from the product of preparation 48 and4-fluoro-2-methylphenylboronic acid, using the method of examples 1-4,as a white foam in 70% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 2.25 (s, 6H), 2.34 (s, 3H), 3.47 (s, 2H), 3.99(s, 3H), 6.86 (d, 1H), 6.93-7.00 (m, 2H), 7.38 (m, 2H), 7.64 (dd, 1H),8.00 (dd, 1H), 8.16 (d, 1H), 8.63 (d, 1H). Microanalysis: C₂₃H₂₃FN₆O0.25H₂O requires; C, 65.31; H, 5.60; N, 19.87. found C, 65.19; H, 5.63;N, 19.58. MS APCl+ m/z 419 [MH]⁺

Example 305-{3-(Ethoxymethyl)-5-[6-(4-fluoro-2-methylphenyl)pyridin-3-yl]-4H-1,2,4-triazol-4-yl}-2-methoxypyridine

The chloro compound of preparation 52 (230 mg, 0.67 mmol), the palladiumcomplex of preparation 3 (10 mg, cat.), caesium carbonate (648 mg, 2.01mmol) and 4-fluoro-2-methylphenylboronic acid (143 mg, 0.94 mmol) weresuspended in 1,4-dioxan (4 mL) and the reaction mixture heated to 110°C. for 2 hours. A further amount of the product of preparation 3 (5 mg)was added and heating continued for 3.5 hours. The mixture was thenpartitioned between ethyl acetate and water, and the organic layer wasseparated, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified HPLC using a Phenomenex Luna C18 system, elutingwith water/acetonitrile/trifluoroacetic acid (5:95:0.1):acetonitrile,95:5 to 5:95 to afford the title compound as a white powder in 16%yield, 44 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 1.16 (t, 3H), 2.35 (s, 3H), 3.54 (q, 2H), 3.99(s, 3H), 4.55 (s, 2H), 6.88 (d, 1H), 6.93-7.00 (m, 2H), 7.34-7.42 (m,2H), 7.56 (dd, 1H), 8.00 (dd, 1H), 8.16 (d, 1H), 8.65 (d, 1H).Microanalysis: C₂₃H₂₂FN₅O₂ 0.5H₂O requires; C, 64.48; H, 5.41; N, 16.35.found C, 64.46; H, 5.27; N, 16.40. MS APCl+ m/z 420 [MH]⁺

Example 314-{5-[5-(Ethoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}-3-methylbenzonitrile

The title compound was prepared from the product of preparation 52 andthe product of preparation 29, using the method of example 30, as abeige solid in 15% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 1.16 (t, 3H), 2.38 (s, 3H), 3.52 (q, 2H), 4.00(s, 3H), 4.55 (s, 2H), 6.89 (d, 1H), 7.43 (d, 1H), 7.49 (d, 1H), 7.58(m, 3H), 8.02 (dd, 1H), 8.17 (d, 1H), 8.70 (d, 1H). Microanalysis:C₂₄H₂₂N₆O₂ 0.5H₂O requires; C, 66.19; H, 5.32; N, 19.30. found C, 66.57;H, 5.17; N, 19.53. MS ES+ m/z 427 [MH]⁺

Example 322-(3,4-Dimethyl-phenyl)-5-[5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrazine

The title compound was prepared from the product of preparation 31 and3,4-dimethylbenzene boronic acid, using the method of example 30. Thecrude compound was purified by column chromatography on silica gel,eluting with dichloromethane:methanol:0.88 ammonia, 96:4:0.4 followed by100% ethyl acetate to afford the desired compound as a beige solid in68% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 2.31 (s, 3H), 2.33 (s, 3H), 3.35 (s, 3H), 4.00(s, 3H), 4.50 (s, 2H), 6.85 (d, 1H), 7.23 (s, 1H), 7.58 (dd, 1H), 7.71(dd, 1H), 7.80 (s, 1H), 8.11 (d, 1H), 8.71 (d, 1H), 9.42 (d, 1H). MSAPCl+ m/z 403 [MH]⁺

Example 334-{4-[5-Methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-phenyl}-2,3-dimethyl-pyridine1-oxide

A mixture of the product of preparation 57 (230 mg, 0.74 mmol),5-amino-2-methoxy pyridine (100 mg, 0.81 mmol) and para-toluenesulfonicacid (30 mg, cat.) in xylene (4 mL) was heated under reflux for 18hours. The mixture was then acidified with 1M hydrochloric acid andwashed with ethyl acetate and the organic layer was discarded. Theaqueous solution was basified with 1M sodium hydroxide solution andextracted with ethyl acetate (×2). The combined organic extracts werewashed with brine, dried over sodium sulfate and concentrated in vacuoto give a brown oil. Purification of the oil by column chromatography onsilica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0to 98:2:0.1, afforded the title compound as a beige foam in 24% yield,74 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.16 (s, 3H), 2.53 (s, 3H), 3.31 (s, 3H), 3.94(s, 3H), 4.43 (s, 2H), 6.81 (d, 1H), 6.94 (d, 1H), 7.19 (m, 2H), 7.49(m, 3H), 8.08 (d, 1H), 8.16 (d, 1H). MS APCl+ m/z 418 [MH]⁺

Example 342-(4-Fluoro-2-methylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]pyridine

The title compound was prepared from the product of preparation 72 and5-amino-2-methoxy pyridine, using the method of example 33, as a brownsolid in 54% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 2.34 (s, 3H), 2.39 (s, 3H), 3.99 (s, 3H),6.87-7.01 (m, 3H), 7.35 (dd, 1H), 7.39 (dd, 1H), 7.45 (dd, 1H), 7.97(dd, 1H), 8.11 (d, 1H), 8.59 (d, 1H). MS APCl+ m/z 376 [MH]⁺

Examples 35 to 45

The following compounds, of the general formula shown below, wereprepared by the method of example 34 using the appropriate oxadiazole(preparations 73-81) and aminopyridine.

The progress of the reactions was monitored by tlc analysis and themixtures were heated under reflux until all of the starting materialshad been consumed.

No. R¹ R² Y Data Yield

35

OCH₃ CH ¹HNMR(CDCl₃, 400 MHz) δ: 2.07(s, 3H), 2.34(s, 3H), 3.32(s, 3H),3.97(s, 3H), 4.38(d, 1H), 4.49(d, 1H), 6.74(d, 1H), 6.95(m, 2H),7.35(dd, 1H), 7.39(d, 1H), 7.50(d, 1H), 8.02(d, 1H), 8.65(d, 1H). MSAPCl+ m/z 420 [MH]⁺ 25% 36

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 2.12(s, 3H), 2.38(s, 3H), 3.32(s, 3H),3.99(s, 3H), 4.39(d, 1H), 4.49(d, 1H), 6.66(d, 1H), 6.99(m, 2H), 7.37(d,1H), 7.39(d, 1H), 8.39(d, 1H), 9.52(d, 1H). MS APCl+ m/z 421 [MH]⁺ 33%37

H N ¹HNMR(CDCl₃, 400 MHz) δ: 2.17(s, 3H), 2.23(s, 3H), 2.44(s, 3H),4.00(s, 3H), 6.64(d, 1H), 7.01(m, 2H), 7.37(m, 2H), 8.37(s, 1H), 9.43(s,1H). MS APCl+ m/z 390 [MH]⁺ 50% 38

H N ¹HNMR(CDCl₃, 400 MHz) δ: 2.15(s, 3H), 2.21(s, 3H), 2.31(s, 3H),2.33(s, 3H), 3.99(s, 3H), 6.68(d, 1H), 7.18(m, 2H), 7.24(m, 1H), 7.33(d,1H), 8.35(d, 1H), 9.50(d, 1H). MS APCl+ m/z 387 [MH]⁺ 36%

39

H N ¹HNMR(CDCl₃, 400 MHz) δ: 2.33(s, 3H), 2.38(s, 3H), 3.82(s, 3H),3.98(s, 3H), 6.41(d, 1H), 6.99(m, 2H), 7.38(dd, 1H), 7.43(d, 1H),8.38(d, 1H), 9.45(d, 1H). MS APCl+ m/z 407 [MH]⁺ 69% 40

H N ¹HNMR(CDCl₃, 400 MHz) δ: 2.21(s, 3H), 2.33(m, 6H), 3.82(s, 3H),3.98(s, 3H), 6.41(s, 1H), 7.21(m, 3H), 7.44(d, 1H), 8.37(d, 1H), 9.44(d,1H). MS APCl+ m/z 403 [MH]⁺ 49%

41

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 2.34(d, 3H), 3.35(s, 3H), 4.00(s, 3H),4.50(s, 2H), 6.85(d, 1H), 7.10(dd, 1H), 7.58(dd, 1H), 7.79(m, 1H),7.87(dd, 1H), 8.11(d, 1H), 8.69(d, 1H), 9.44(d, 1H) MS APCl+ m/z 407[MH]⁺ 33% 42

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 3.36(s, 3H), 3.93(s, 3H), 4.01(s, 3H),4.51(s, 2H), 6.86(d, 1H), 7.06(dd, 1H), 7.21(dd, 1H), 7.57(m, 2H),8.11(d, 1H), 8.79(d, 1H), 9.51(d, 1H) MS APCl+ m/z 423 [MH]⁺ 40% 43

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 2.34(s, 3H), 3.35(s, 3H), 3.83(s, 3H),4.00(s, 3H), 4.50(s, 2H), 6.85(d, 1H), 6.89(d, 1H), 7.19-7.26(m, 1H),7.59(dd, 1H), 7.68(s, 1H), 8.12(d, 1H), 8.91(s, 1H), 9.44(d, 1H). MSAPCl+ m/z 419 [MH]⁺ 31% 44

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 3.35(s, 3H), 3.85(s, 3H), 4.00(s, 3H),4.50(s, 2H), 6.85(d, 1H), 6.93(d, 1H), 7.10(m, 1H), 7.59(dd, 1H),7.69(s, 1H), 8.12(d, 1H), 8.96(s, 1H), 9.47(d, 1H). MS APCl+ m/z 423[MH]⁺ 39% 45

OCH₃ N ¹HNMR(CDCl₃, 400 MHz) δ: 2.33(s, 3H), 2.34(s, 3H), 3.35(s, 3H),4.00(s, 3H), 4.50(s, 2H), 6.85(d, 1H), 7.17(dd, 2H), 7.24(m, 1H),7.60(dd, 1H), 8.13(d, 1H), 8.43(d, 1H), 9.48(d, 1H). MS APCl+ m/z 403[MH]⁺ 41%

Example 42

crude product was re-purified by column chromatography on silica gel,eluting with ethyl acetate:methanol, 98:2.

Examples 35, 37, 38, 41, 43, 44 and 45

crude products were purified by trituration with diethyl ether.

Example 465-{3-[5-(4-Fluoro-2-methyl-phenyl)-pyrazin-2-yl]-5-methyl-[1,2,4]triazol-4-yl}-pyridin-2-yl)-methyl-amine

A mixture of the product of preparations 74 (437 mg, 1.62 mmol) and 83(434 mg, 3.52 mmol) and para-toluenesulfonic acid in xylene (10 mL) washeated under reflux for 100 hours. The mixture was then filtered throughCelite®, washing through with dichloromethane and the filtrate wasconcentrated in vacuo. Purification by column chromatography on silicagel, eluting with dichloromethane:methanol:0.88 ammonia, 98:2:0.2,followed by ethyl acetate:methanol, 98:2, afforded the title compound asa beige solid in 9% yield, 57 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.38 (m, 6H), 2.98 (d, 3H), 4.89 (m, 1H), 6.47(d, 1H), 6.94-7.02 (m, 2H), 7.36 (m, 2H), 7.97 (d, 1H) 8.43 (s, 1H),9.41 (d, 1H). MS APCl+ m/z 376 [MH]⁺

Example 473-(4-Fluoro-2-methyl-phenyl)-6-[5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridazine

The product of preparation 62 (40 mg, 0.13 mmol),5-amino-2-methoxypyridine (16 mg, 0.13 mmol) and para-toluenesulfonicacid monohydrate (5 mg, cat) were dissolved in xylene (2 mL) and thereaction mixture was heated under reflux for 3 hours. The reactionmixture was then partitioned between dichloromethane and sodium hydrogencarbonate solution and the organic solution was washed with brine, driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby HPLC using a Phenomenex Luna C18 system, eluting withwater/acetonitrile/trifluoroacetic acid (5:95:0.1):acetonitrile, 95:5 to5:95 to afford the title compound as a yellow oil in 8% yield, 4 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.33 (s, 3H), 3.36 (s, 3H), 3.94 (s, 3H), 4.52(s, 2H), 6.83 (d, 1H), 7.02 (m, 2H), 7.39 (d, 1H), 7.70 (m, 2H) 8.11 (s,1H), 8.46 (d, 1H).

Example 485-(4-Fluoro-2-methyl-phenyl)-2-[5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyrimidine

The product of preparation 69 (80 mg, 0.27 mmol),5-amino-2-methoxypyridine (50 mg, 0.39 mmol) and para-toluenesulfonicacid monohydrate (10 mg, cat) were dissolved in xylene (3 mL) and thereaction mixture was heated under reflux for 18 hours. Additionalpara-toluenesulfonic acid monohydrate (10 mg, cat) was added and heatingcontinued for a further 18 hours. The reaction mixture was thenevaporated under reduced pressure and the residue was dissolved in ethylacetate, washed with 1M hydrochloric acid, sodium hydrogen carbonatesolution and brine, dried over magnesium sulfate and concentrated invacuo. Purification of the residue by column chromatography on silicagel, eluting with dichloromethane:methanol, 97:3, afforded the titlecompound in 46% yield, 49.3 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.23 (s, 3H), 3.32 (s, 3H), 3.99 (s, 3H), 4.51(s, 2H), 6.82 (d, 1H), 6.98 (m, 2H), 7.17 (d, 1H), 7.60 (d, 1H), 8.11(s, 1H), 8.67 (s, 2H). MS APCl+ m/z 407 [MH]⁺

Examples 49 to 52

The following compounds, of the general formula shown below, wereprepared by the method of example 48, using the product of preparation71 and the appropriate boronic acid.

No. R¹ Data Yield 49

¹HNMR(CDCl₃, 400 MHz) δ: 2.20 (s, 3H), 2.30(s, 3H), 3.79(s, 3H), 3.95(s,3H), 6.38(d, 1H), 6.88-6.98 (m, 2H), 7.10(dd, 1H), 7.42(d, 1H), 7.65(dd,1H), 8.19(d, 1H), 8.21(d, 1H). MS APCl+ m/z 406 [MH]⁺ 50% 50

¹HNMR(CDCl₃, 400 MHz) δ: 2.09 (s, 3H), 2.30(s, 3H), 2.39(s, 3H), 3.80(s,3H), 3.96(s, 3H), 6.39(d, 1H), 6.98(d, 1H), 7.09-7.02(m, 2H), 7.46(d,1H), 7.68(d, 1H), 8.19(d, 1H), 8.24(d, 1H). MS APCl+ m/z 402 [MH]⁺ 50%51

MS APCl+ m/z 422 [MH]⁺ 69% 52

MS APCl+ m/z 406 [MH]⁺ 46%

Example 533-{5-[4-(6-Methoxy-pyridin-3-yl)-5-methyl-4H-[1,2,4]triazol-3-yl]-pyrazin-2-yl}-4-methyl-benzonitrile

A mixture of 3-chloro-4-methylbenzonitrile (1 g, 6.6 mmol),bis(pinacolato)diboron (1.8 g, 7.0 mmol), caesium carbonate (6.4 g, 19.8mmol) and the product of preparation 3 (5 mg, cat) in 1,4-dioxan (50 mL)was heated under reflux for 4 hours. The reaction mixture was thencooled to room temperature, filtered through Celite® and concentrated invacuo.

A portion of the residue (145 mg, 0.6 mmol), the product of preparation30 (90 mg, 0.3 mmol), caesium carbonate (293 mg, 0.9 mmol) and theproduct of preparation 3 (2 mg, cat) were then dissolved in 1,4-dioxanand the mixture was heated under reflux for 18 hours. The mixture wasthen cooled to room temperature, filtered through Celite® andconcentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with dichloromethane:methanol,100:0 to 97:3, afforded the title compound as a white solid in 3% yield,3 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.41 (s, 3H), 2.46 (s, 3H), 4.02 (s, 3H), 6.90(d, 1H), 7.43 (d, 1H), 7.53 (dd, 1H), 7.63 (dd, 1H), 7.70 (d, 1H), 8.09(d, 1H), 8.41 (d, 1H), 9.55 (d, 1H). MS APCl+ m/z 383 [MH]⁺

Example 542-(4-Fluoro-2-methyl-phenyl)-4-methoxy-5-[5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridine

A mixture of the product of preparations 90 (60 mg, 0.17 mmol) and 3 (10mg, cat), 4-fluoro-2-methylbenzene boronic acid (33 mg, 0.21 mmol) andcaesium carbonate (110 mg, 0.34 mmol) in dioxan (4 mL) was heated underreflux for 16 hours. Catalytic amounts of 4-fluoro-2-methylbenzeneboronic acid and the product of preparation 3 were then added to thereaction mixture and heating continued for a further 3 hours. Themixture was diluted with dichloromethane and was purified directly bycolumn chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 96:4, to obtain the title compound asa white foam in 54% yield, 39 mg.

¹HNMR (CDCl₃, 400 MHz) δ: 2.34 (s, 3H), 3.39 (s, 3H), 3.62 (s, 3H), 3.94(s, 3H), 4.51 (s, 2H), 6.77 (m, 2H), 6.96 (m, 2H), 7.33 (dd, 1H), 7.50(dd, 1H), 8.05 (d, 1H), 8.70 (d, 1H). MS APCl+ m/z 436 [MH]⁺

Example 552-(5-Fluoro-2-methoxy-phenyl)-4-methoxy-5-[5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridine

The title compound was prepared from the product of preparation 90 and5-fluoro-2-methoxybenzene benzoic acid, using the method of example 54,as a yellow foam in 53% yield.

¹HNMR (CDCl₃, 400 MHz) δ: 3.39 (s, 3H), 3.63 (s, 3H), 3.83 (s, 3H), 3.93(s, 3H), 4.51 (s, 2H), 6.76 (d, 1H), 6.93 (dd, 1H), 7.07 (m, 1H), 7.41(s, 1H), 7.49 (dd, 1H), 7.63 (dd, 1H), 8.04 (d, 1H), 8.70 (s, 1H). MSAPCl+ m/z 452 [MH]⁺

Example 562-(3-Fluoro-2-methoxy-phenyl)-5-[4-(6-methoxy-pyridin-3-yl)-5-methyl-4-H-[1,2,4]triazol-3-yl]-pyrazine

The title product was prepared by the method of example 14 using thechloro compound of preparation 30 (108 mg, 0.32 mmol) and2-methoxy-3-fluoro-benzene boronic acid (72 mg, 0.48 mmol). 107 mg, 79%yield of the title product was prepared as a white solid.

¹HNMR (CDCl₃, 400 MHz) δ: 3.35 (s, 3H), 3.85 (s, 3H), 4.00 (s, 3H), 4.5(s, 2H), 6.85 (d, 1H), 7.20 (m, 2H), 7.60 (m, 2H), 8.15 (s, 1H), 8.85(s, 1H), 9.50 (s, 1H). Microanalysis: C₂₁H₁₉FN₆O₃ 0.2H₂O requires; C,59.21; H, 4.59; N, 19.73. found C, 59.27; H, 4.69; N, 19.33. MS APCl+m/z 423 [MH]⁺

1. A compound of formula (I)

wherein X and Y are each N; V and W are each C—R⁶; Z is C—H or N; R¹ isselected from: (i) a phenyl ring substituted with two or moresubstituents, which may be the same or different, each independentlyselected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, C(O)NR⁷R⁸,NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂; and (ii) a five to seven memberedaromatic heterocyclic ring containing 1-3 hetero atoms selected from N,O and S; said ring being optionally substituted with two or moresubstituents, which may be the same or different, selected from halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ andN[C(O)R¹⁰]₂; R² is selected from: (i) H, OH, OR⁹, NR⁷R⁸, NR⁷C(O)R¹⁰ andN[C(O)R¹⁰]₂; (ii) a 5-7 membered N-linked heterocycle containing 1-3heteroatoms selected from N, O and S; said ring being optionallysubstituted with one or more groups selected from (C₁-C₆)alkyl,(C₁-C₆)alkoxy and C(O)NR⁷R⁸; and (iii) (C₁-C₆)alkyl optionallysubstituted with an N-linked 5-7 membered heterocycle containing 1-3heteroatoms selected from N, O and S; R³ is selected from H and(C₁-C₆)alkyl; R⁴ is selected from H, (C₁-C₆)alkyl and OR⁹; R⁵ isselected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, NR⁷R⁸, NR⁷C(O)R¹⁰ andN[C(O)R¹⁰]₂; R⁶ is selected from H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,cyano, NR⁷R⁸, NR⁷C(O)R¹⁰, N[C(O)R¹⁰]₂ and C(O)NR⁷R⁸; R⁷ and R⁸, whichmay be the same or different, are selected from H and (C₁-C₆)alkyl; R⁹is (C₁-C₆)alkyl, which is optionally substituted with one or more groupseach independently selected from (C₁-C₆)alkoxy and an N-linked 5-7membered heterocycle containing 1-3 heteroatoms selected from N, O andS; and R¹⁰ is selected from (C₁-C₆)alkyl and (C₁-C₆)alkoxy; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 wherein V and W are each CH; or a pharmaceutically acceptablesalt thereof.
 3. The compound according to claim 1 wherein Z is N; or apharmaceutically acceptable salt thereof.
 4. The compound according toclaim 1 wherein Z is CH; or a pharmaceutically acceptable salt thereof.5. The compound according to claim 1 wherein R¹ is selected from: (i) aphenyl ring substituted with two substituents, which may be the same ordifferent, each independently selected from halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, cyano, C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂; and(ii) a pyridyl ring substituted with two substituents, which may be thesame or different, each independently selected from halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, cyano, C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂; or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 5 wherein R¹ is a phenyl ring substituted with two substituents,which may be the same or different, each independently selected fromfluoro, chloro, methyl, methoxy and cyano; or a pharmaceuticallyacceptable salt thereof.
 7. The compound according to claim 5 wherein R²is selected from: (i) H, (C₁-C₃)alkoxy, (C₁-C₃)alkoxy-(C₁-C₃)alkoxy andN((C₁-C₃)alkyl)₂; and (ii) a 5 membered N-linked heterocycle containing1-3 nitrogen atoms, said ring optionally substituted with C(O)NR⁷R⁸; ora pharmaceutically acceptable salt thereof.
 8. The compound according toclaim 7 wherein R¹ is a phenyl ring substituted with two substituents,which may be the same or different, each independently selected fromfluoro, chloro, methyl, methoxy and cyano; or a pharmaceuticallyacceptable salt thereof.
 9. The compound according to claim 8 wherein R²is selected from H, methoxy, ethoxy, 2-methoxyethoxy, dimethylamino,1,2,3-triazol-2-yl and pyrrolidinyl, wherein said pyrrolidinyl isoptionally substituted by CONH₂; or a pharmaceutically acceptable saltthereof.
 10. The compound according to claim 9 wherein R² is selectedfrom H and methoxy; or a pharmaceutically acceptable salt thereof. 11.The compound according to claim 10 wherein R³ is H; or apharmaceutically acceptable salt thereof.
 12. The compound according toclaim 11 wherein R¹ is a phenyl ring substituted with two substituents,which may be the same or different, each independently selected fromfluoro, chloro, methyl, methoxy and cyano; or a pharmaceuticallyacceptable salt thereof.
 13. The compound according to claim 12 whereinR⁴ is H, methyl or methoxy; or a pharmaceutically acceptable saltthereof.
 14. The compound according to claim 13 wherein R¹ is a phenylring substituted with two substituents, which may be the same ordifferent, each independently selected from fluoro, chloro, methyl,methoxy and cyano and R² is selected from H, methoxy, ethoxy,2-methoxyethoxy, dimethylamino, 1,2,3-triazol-2-yl and pyrollidinyl, thelatter being optionally substituted by CONH₂; or a pharmaceuticallyacceptable salt thereof.
 15. The compound according to claim 14 whereinR⁴ is H.
 16. A compound according to claim 1, which is3-(4-Fluoro-2-methyl-phenyl)-6-[5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridazine;or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising a compound of formula (I) as claimed in claim 1or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.
 18. A method of palliatively treatingmale sexual dysfunction, female sexual dysfunction, hypoactive sexualdesire disorder, sexual arousal disorder, orgasmic disorder, sexual paindisorder, or premature ejaculation in a mammal, the method comprisingadministering a therapeutically effective amount of a compound of claim1 or a pharmaceutically acceptable salt thereof to a mammal in need oftreatment thereof.
 19. The method according to claim 18 wherein sexualarousal disorder, orgasmic disorder, sexual pain disorder or prematureejaculation is treated.